Physiol Rev
83: 1069 –1112, 2003; 10.1152/physrev.00005.2003.
Role of Monocytes in Atherogenesis
BJARNE ØSTERUD AND EIRIK BJØRKLID
Department of Biochemsitry, Institute of Medical Biology, Faculty of Medicine,
University of Tromsø, Tromsø, Norway
1070
1070
1072
1072
1072
1073
1075
1075
1076
1077
1077
1077
1079
1080
1080
1080
1081
1083
1086
1086
1086
1087
1088
1090
1092
1092
1093
1093
1094
1095
1095
1097
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
I. Introduction
II. Initiation of Atherosclerosis
III. Experimental Evidence That Monocyte Recruitment to the Intima Is Linked to Atherogenesis
A. Early monocyte recruitment to the intima
B. Role of adhesion molecules
C. Role of chemoattractants
IV. Role of Low-Density Lipoprotein
A. Early, low-grade events
B. Modulation of LDL
C. Proinflammatory reactions associated with LDL oxidation
V. Monocyte Differentiation and the Role of the Extracellular Matrix in Atherogenesis
A. Macrophage formation
B. Foam cell formation
C. Roles of extracellular matrix and metalloproteinases in atherogenesis
VI. Monocytes/Macrophages and the Role of Their Activation Products
A. Regulation of activation
B. Autocrine- and paracrine-mediated activation reactions in monocytes
C. Roles of cytokines produced by monocytes/macrophages
D. CD14 polymorphism on the gene of the CD14 receptor
VII. Cellular Signals Involved in Monocyte Activation
A. Role of phospholipases
B. Role of phospholipases in atherosclerosis
C. Pathways for arachidonic acid conversion
D. Role of lipoxygenases in atherogenesis
E. Availability of arachidonic acid
F. PAF
G. Eicosanoid products involved in the activation of monocytes?
H. PPAR-␥ as regulator of monocyte/macrophage function
VIII. Infection, Monocytes, and Atherosclerosis
A. C-reactive protein and its relation to atherosclerosis
IX. The Proinflammatory Platelet and Its Role in the Early Phase of Atherogenesis
X. Conclusions
Østerud, Bjarne, and Eirik Bjørklid. Role of Monocytes in Atherogenesis. Physiol Rev 83: 1069 –1112, 2003; 10.1152/
physrev.00005.2003.—This review focuses on the role of monocytes in the early phase of atherogenesis, before foam cell
formation. An emerging consensus underscores the importance of the cellular inflammatory system in atherogenesis.
Initiation of the process apparently hinges on accumulating low-density lipoproteins (LDL) undergoing oxidation and
glycation, providing stimuli for the release of monocyte attracting chemokines and for the upregulation of endothelial
adhesive molecules. These conditions favor monocyte transmigration to the intima, where chemically modified, aggregated, or proteoglycan- or antibody-complexed LDL may be endocytotically internalized via scavenger receptors present
on the emergent macrophage surface. The differentiating monocytes in concert with T lymphocytes exert a modulating
effect on lipoproteins. These events propagate a series of reactions entailing generation of lipid peroxides and expression
of chemokines, adhesion molecules, cytokines, and growth factors, thereby sustaining an ongoing inflammatory process
leading ultimately to lesion formation. New data emerging from studies using transgenic animals, notably mice, have
provided novel insights into many of the cellular interactions and signaling mechanisms involving monocytes/macrophages in the atherogenic processes. A number of these studies, focusing on mechanisms for monocyte activation and the
roles of adhesive molecules, chemokines, cytokines and growth factors, are addressed in this review.
www.prv.org
0031-9333/03 $15.00 Copyright © 2003 the American Physiological Society
1069
1070
BJARNE ØSTERUD AND EIRIK BJØRKLID
I. INTRODUCTION
Physiol Rev • VOL
II. INITIATION OF ATHEROSCLEROSIS
Atherogenic lesions have been observed to arise at
regions of the vessel wall exhibiting endothelial activation. Possible causes of such activation comprise elevated
and modified LDL, free radicals arising during oxidative
stress and cigarette smoking, hypertension, diabetes mellitus, genetic alterations, hyperactive monocytes/platelets, chronic infections such as by microorganisms like
herpes viruses, Chlamydia pneumonia or others, and
obviously combinations of these or as yet unrecognized
factors (for a review, see Ref. 444). LDL, which may be
modified by oxidation, glycation, and aggregation, or incorporated into immune complexes (254, 255, 370, 499), is
a major culprit, initiating the signals which promote the
recruitment and accumulation of monocytes and T lymphocytes (186, 346, 370). Neutrophils may also have a role
in the very early immune response (143).
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
Three cellular components of the circulation, monocytes, platelets, and T lymphocytes, together with two cell
types of the artery wall, endothelial and smooth muscle
cells (SMC), interact in multiple ways in concert with
low-density lipoprotein (LDL)-cholesterol in generating
atherosclerotic lesions. The major objective of this review
is to focus on the early phase of the development of
atherosclerosis, i.e, the formation of fatty streaks (lesions) in the vessel wall, with an emphasis on the roles of
monocytes and lipid oxidation.
Recruitment of monocytes and lymphocytes from the
peripheral blood to the intima of the vessel wall is a
primordial event in atherogenesis (see sect. IIIA), an event
that appears to depend on the local presence of high
amounts of LDL. As the LDL accumulates, their lipids and
proteins undergo oxidation and glycation. Cells in the
vessel wall seem to interpret the change as a danger sign,
and they call for reinforcement from the body’s defense
system. These events appear to promote upregulation of
adhesion molecules on the endothelial cells (EC), particularly vascular cell adhesion molecule-1 (VCAM-1) and
intercellular adhesion molecule-1 (ICAM-1). Thus monocyte and lymphocyte recruitment is initiated, leading to
enhanced transmigration of monocytes, upregulated exposure of adhesion molecules on a variety of cells (see
sect. IIIB), and chemoattractant production and release
(see sect. IIIC). These are all essential elements of the
transfer of monocytes to the intima and the concurrent
differentiation of these cells into macrophages. Available
LDL is a prerequisite for the further conversion of macrophages into lipid-loaded macrophages, major residents
of the fatty streak formed just underneath the endothelium of the vessel wall. LDL and its modified forms (oxidized, acylated, etc.; see sect. IV, A and B) are of particular
interest, since the modification of LDL is associated with
inflammatory reactions (see sect. IVC), amplifying proinflammatory events already initiated due to the adherence
and transmigration of monocytes and lymphocytes into
the intima.
The emerging notion that chronic infections may unleash atherogenic trigger mechanisms (see sect. VIII) is
suggestive of a very important role of monocytes in lesion
formation by way of their proficiency in generating proinflammatory products. This warrants focus on the cellular
signal transduction network of monocyte activation, including the early phase entailing phospholipase activation
and release of arachidonic acid (see sect. VII). Transgenic
mice have opened access to a substantial body of information regarding the roles of the various signal-systems
of importance in atherosclerosis (see sects. III, A and B,
IVC, VB, VIC, and VII, B–D). Much of the work has focused
on the enzymes involved in the conversion of arachidonic
acid to leukotrienes and hydroxyfatty acids (lipoxygen-
ases; see sect. VII, C and D) and prostaglandins (cycloxygenases; see sect. VIIC), lending support to the notion that
lipoxygenases may have a vital role in lesion formation
(see sect. VIID), whereas the cyclooxygenases appear less
important. According to recent evidence, the thromboxane A2 (TxA2) receptor may have an important function in
promoting lesion formation (see sect. VIIG), unrelated to
the binding of its major ligand, as demonstrated by the
noninterference of acetyl salicylic acid (ASA).
In order that monocytes may promote atherosclerosis, a number of unfavorable factors or conditions may
have to merge. Polymorphism of the gene of the monocyte CD14 receptor (see also sect. VID) may be part of the
explanation why there are major risk factors unrelated to
high cholesterol. This receptor mediates not only the
toxic effects of bacteria (lipopolysaccharide; LPS) in
chronic infections (e.g., Chlamydia pneumonia), but also
the cytokine-like effect of heat shock proteins, which is
associated with coronary heart disease (CHD) (see sect.
VIII). Platelet activating factor (PAF) (see sect. VIIF) and
cytokines, particularly tumor necrosis factor-␣ (TNF-␣),
interleukin (IL)-1␤, IL-6 (see sect. VIC), and growth hormones, promote the inflammatory reactions associated
with atherogenesis. Another significant regulator of
monocyte/macrophage function is the peroxisome proliferator-activated receptor-␥ (PPAR␥), studies on which
might shed further light on processes central to atherogenesis (see sect. VIIH).
It has not been the intention in this article to cover all
aspects of atherosclerosis. For example, changes in the
endothelium during atherogenesis, the role of smooth
muscle cells and their interactions with macrophages, T
lymphocytes, and fibroblasts and their activation products, prominent in the later phase of atherogenesis, have
not been presented. Furthermore, the events leading to
plaque rupture and thrombosis have not been included.
MONOCYTES IN ATHEROGENESIS
Physiol Rev • VOL
and the subsequent immune responses (1). This scenario
is in accordance with the observation that atherosclerotic
lesions are rich in immunoglobulins, which can be found
in proximity to macrophages even in very early fatty
streaks (390). These immunoglobulins comprise specific
autoantibodies to neoepitopes arising during oxidative or
other types of injury, some of which have been identified
in immune complexes incorporating oxidized LDL (583).
The emerging lesson from transgenic mouse models
is that monocytes and macrophages partake crucially in
the development of atherosclerotic lesions, whereas results pertaining to T and B cells are more ambiguous and
model dependent, suggesting that under certain conditions these cell types may also promote lesion formation
(430, 491).
The enrichment of white blood cells in lesion-prone
areas has been shown to be of primarily mononuclear
origin (98, 439, 483, 549, 587). The prevalence of such
changes has been affirmed in a normocholesterolemic
rabbit model, where adhered white blood cells were detected in the lesion-prone flow divider regions of the large
abdominal branches (320). Interestingly, lesion-rich aortic
and coronary artery segments had significantly greater
numbers of mast cells in the adventitia compared with
those with a normal intima (19). In normal aortic segments, higher numbers of mast cells were located in the
lesion-prone than in the lesion-deficient regions. These
observations seem to suggest that part of the proatherogenic potential latent in a vessel wall derives from mast
cells and their released products, such as histamine and
tryptase.
The model of atherogenesis initiation outlined above
is mainly based on experimental animal models with high
rate of developing lesions, i.e., fat-fed and genetically
hyperlipidemic animals. One may therefore question the
validity of such animal models regarding the uptake of
oxidized LDL and the effects exerted by oxidized LDL. In
line with this skepticism is the proposal of a concept of
lesions arising in preexisting intimal masses (465): “Given
the evidence for a concordance of the distribution of
lesions in adult humans, it seems likely that some property of the intimal cells accounts for localization of lesions.” Perhaps the simplest hypothesis, as put forward by
Williams and Tabasas (565), is that cells making up the
intimal masses have special properties and contribute to
lipid accumulation at focal sites. Whether these intimal
cells are part of the intimal cellular infiltration and connective tissue described in the coronary arteries of male
children, adolescents and young adults remains to be
clarified. Interestingly, black people and women have less
than average cellular infiltration and connective tissue in
their arteries. Whatever factors that are favoring LDL
oxidation and macrophage lipid accumulation and retention, even at normal plasma LDL levels, might explain
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
Such recruitment of leukocytes continues for as long
as hypercholesterolemic conditions prevail (362), without
any apparent impairment of the vascular endothelium, the
latter contributing to leukocyte recruitment by upregulated expression of specific leukocyte adhesion molecules, notably VCAM-1 and ICAM-1 (see sect. III). In baboons, monocyte margination or attachment observed
over normal vessel areas or over plaques was not associated with morphological evidence of endothelial injury,
whether under normal or hypercholesterolemic conditions. Migration of these cells through continuous aortic
endothelium occurred primarily at junctional sites, between endothelial cells (464). Furthermore, strong interaction between monocytes and components of the extracellular matrix (ECM), e.g., collagen and proteoglycans, is
probably a prerequisite for the formation of lipid-laden
macrophages (foam cells) (238).
LDL particles trapped in the artery are prone to advancing oxidation, rendering them recognizable by scavenger receptors present on the surface of macrophages
and thus targets for internalization by these cells (186,
201, 255, 346, 370, 499), a process ultimately leading to the
formation of foam cells. The extent of LDL modification
and hence the vigor of this rampant process may vary
greatly (123, 186, 370). LDL modified and taken up by the
macrophages activates the nascent foam cells, inducing
release of inflammatory mediators such as TNF-␣, IL-1␤,
IL-8, and macrophage colony stimulating factor (MCSF).
This release in turn leads to increased transcription of the
LDL-receptor gene and consequently enhanced binding of
LDL to the endothelium and smooth muscle cells (194,
503), feeding the process even further.
Part of the proinflammatory effect of modified LDL
on endothelial cells indirectly derives from its chemotactic effect on monocytes (105), and furthermore, it can
upregulate the endothelial cell genes for MCSF and monocyte chemotactic protein-1 (MCP-1) (478). Either mechanism elicits an expanding number of monocyte-derived
macrophages populating the artery wall.
The arterial wall may be subject to immunological
injury leading to conditions favoring atherosclerosis development (81). Recent studies have implicated several
immune complexes as proatherogenic. The fatty streak
type of lesion typical of the earliest stage, frequently
occurring in infants and young children (367), is of a
purely inflammatory process involving only monocytederived macrophages and T lymphocytes (497). Thus the
attachment of monocytes and T lymphocytes to the endothelium followed by their migration into the intima is
one of the first and most crucial steps in lesion development. Immune complex-bound antigens taken up by
phagocytes via Fc receptors are processed and presented
to T cells in the context of major histocompatibility complex (MHC) class I or II molecules. Such antigen processing and presentation greatly enhance T-cell stimulation
1071
1072
BJARNE ØSTERUD AND EIRIK BJØRKLID
the emergence of the initial cluster of macrophage foam
cells (336).
III. EXPERIMENTAL EVIDENCE THAT
MONOCYTE RECRUITMENT TO THE
INTIMA IS LINKED TO ATHEROGENESIS
A. Early Monocyte Recruitment to the Intima
Physiol Rev • VOL
B. Role of Adhesion Molecules
1. Selectins and VCAM-1
The most comprehensive body of evidence for an
important role of adhesion molecules in atherogenesis
has emerged from various studies using transgenic mice
and a few transgenic rabbit models (286). Thus strong
evidence that P-selectin is critically involved in initiation
of the process was recently reported based on studies
using P-selectin-deficient mice (P ⫺/⫺) back-crossed
onto a C57BL16 background (133). When subjected to a
high-fat diet for 20 wk, these mice were significantly less
prone to fatty streak formation than were the wild type.
Fatty streaks are the first visible sign that foam cells
accumulate within the intima, close to the surface of the
vessel wall. Furthermore, in the same study, the hypercholesterolemia-prone offspring of P-selectin deficiency
(P ⫺/⫺) animals or a combination of P-and E-selectin
deficiency (P/E ⫺/⫺) animals interbred with mice lacking
the LDL receptor (LDLR ⫺/⫺), were fed an atherogenic
diet for 8, 20 –22, and 37 wk. At 8 wk, mice with combined
P ⫺/⫺ and LDLR ⫺/⫺ had developed significantly smaller
fatty streaks than was evident in their half-siblings expressing P-selectin. However, after a more prolonged exposure to the high-fat diet and progression of the lesions
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
An initial event in atherogenesis is endothelial cell
activation, probably mediated by atherogenic lipoproteins
such as remnants, modified LDL or oxidized LDL, particularly potent forms of which are those modified by oxidation or glycation (in diabetes) or trapped in immune
complexes. Such activation of the endothelium causes
upregulation of endothelial cell adhesion molecules and
selectins, promotion of oxygen radical formation, increased apoptosis, and reduced endothelium-dependent
relaxation.
The multistep process of localized accumulation of
leukocytes, which is regulated by the expression of specific adhesion molecules, may leave the endothelium unperturbed. Thus focal recruitment and attachment of
monocytes, whether over plaques or normal areas, was
not associated with evidence of endothelial injury as
shown in normo- and hypercholesterolemic baboons
(464). In addition to monocyte recruitment, lymphocyte
recruitment is one of the earliest detectable cellular responses in the process leading to the formation of atherosclerotic lesions.
In a transgenic mouse model, two types of endothelial cell-derived adhesion molecules, VCAM-1 and ICAM-1,
were shown to play an important role at sites where
lesions eventually form (231, 362). Thus homozygous apolipoprotein E-deficient (Apo E ⫺/⫺) mice that develop
atherosclerotic lesions much like those found in humans
were compared with normal control mice. Whereas in the
latter specific VCAM-1 staining was weak and limited to
sites of altered blood flow, in the Apo E ⫺/⫺ mice significant amounts of VCAM-1 appeared to be localized across
the surface of EC at lesion-prone sites. The expression of
VCAM-1 preceded lesion formation and correlated positively with the extent of exposure to plasma cholesterol.
ICAM-1 too was expressed across the surface of EC and
microvilli at lesion-prone sites, but at a rate insensitive to
plasma cholesterol levels. Similarly, in a recent study,
recruitment of circulating white blood cells by endothelial
adhesion molecules was suggested to be more important
during lesion initiation than during the late phase of rapid
lesion growth (294). In rabbits, similar upregulation of
endothelial adhesion molecules at lesion-prone as well as
already atherosclerotic sites has been reported (231).
There is supporting evidence that many of these adhesion molecules are expressed by cells in human and
experimental atherosclerotic lesions and that expression
of adhesion molecules such as VCAM-1 is temporally
related to lesion initiation and progression in animal models (for commentary, see Ref. 443).
The mechanism whereby LDL interacts with the endothelium is not quite understood. In one study it was
shown that binding of native LDL (n-LDL) to the LDL
receptor triggers a rise in intracellular calcium which acts
as a second messenger in inducing VCAM-1 expression in
human coronary aortic cells (9).
VCAM-1 expressed before leukocyte accumulation
can initiate both monocyte and lymphocyte tethering and
rolling (for leukocyte recruitment at the endothelium, see
excellent review by Ley, Ref. 297) and can induce firm
adhesion in the absence of chemoattractants. ICAM-1 exposed on microvilli at lesion-prone sites enhances firm
adhesion of leukocytes that have reached the primary,
transient adhesion step, whereas ICAM-1 more strongly
expressed across the endothelial surface promotes cellular arrest where cell-cell contact has already been established. Finally, transendothelial leukocyte migration entailing subendothelial homing and formation of early fatty
streaks is supported by the universally expressed plateletendothelial cell adhesion molecule-1 (PECAM-1) and also
possibly enhanced by locally expressed VCAM-1 (362).
A more detailed account of the evidence for the
functional role of adhesion molecules and chemokines in
disease models is given below.
MONOCYTES IN ATHEROGENESIS
2. Integrins and ligands
In rats subjected to dietary-induced hypercholesterolemia, ICAM-1 expression was upregulated mainly in the
lesion-prone areas of aorta during the early stages of
atherogenesis. This was associated with a pronounced
recruitment of monocytes and T lymphocytes to the intima (552). Prior injections of specific antibodies to ICAM1/lymphocyte function antigen-1 (LFA-1) significantly reduced monocyte adherence and migration into the intima.
In another study, ApoE-deficient mice (apo E ⫺/⫺)
maintained on an atherogenic Western diet were subjected to arterial injury, and posttrauma effects of the
Physiol Rev • VOL
concurrent presence of additional ICAM-1 or P-selectin
deficiencies were investigated (325). After 5 wk, a Pselectin deficiency linked 94% inhibition of neointima formation was found, whereas ICAM-1 deficiency gave no
discernible protection against injury-induced plaque formation in these mice. It was concluded that absence of
P-selectin but not of ICAM-1 reduces the plaque area and
that P-selectin is critical for monocyte recruitment to sites
of neointima formation after arterial injury.
Very late antigen 4 (VLA-4) is the ligand for VCAM-1
and fibronectin containing segment-1 (CS-1) (86, 138, 189,
555) (Table 1). Evidence has been found favoring the
notion that VLA-4 has an important role in regulating
leukocyte entry into early (479) as well as advanced (397)
lesions. It was suggested that the VLA-4 integrin plays an
important role in the initial phase of atherosclerotic lesion
formation and lipid accumulation (479). According to the
evidence currently available, it seems plausible that Pselectin and its ligand PSGL-1 together with VCAM-1 and
its ligand VLA-4 may be the most important adhesion
molecules involved in monocyte recruitment to atherosclerotic lesions (228).
3. Other factors
Von Willebrand factor (vWF) has been suggested to
be potentially proatherogenic, due to its important role in
platelet functioning (114, 164, 504) and in regulating factor VIII in blood (339, 343). Evidence in support of this
notion was recently found in studies using transgenic
mice deficient in the LDLR (LDLR ⫺/⫺) as well as vWF
(vWF ⫺/⫺). When fed a Chow diet, these double deficiency mice had a 50% reduction in leukocyte rolling
compared with rats with the LDLR ⫺/⫺ trait only, dropping to 20% when an atherogenic fat diet was given (342).
The high reduction in leukocyte rolling when a Chow diet
was administered was associated with a 50% size reduction of lesions in the aortic sinus. Furthermore, between
the superior mesenteric artery and the renal artery, vWF
⫺/⫺ animals were markedly less liable to lesion formation than were wild-type ones.
A list of adhesion molecules and ligands and their
leukocyte and endothelial cell targets is shown in Table 1.
C. Role of Chemoattractants
Certain adhesion molecules are currently seen as
essential for the recruitment of monocytes to the intima.
However, according to several studies it appears that a
number of additional factors including several chemoattractants are needed in the orchestration of the process
(for reviews, see Refs. 27, 315, 428). The most relevant
chemoattractants pertaining to atherogenesis will be discussed in the following sections.
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
to the fibrous plaque stage, the two forms of offspring
were no longer discernibly different.
LDLR ⫺/⫺ offspring deficient also in P-selectin as
well as E-selectin were even more profoundly protected
against lesion development, even into the fibrous plaque
stage (205).
Apo E-deficient mice spontaneously develop lesions
when fed a normal Chow diet. They have very high cholesterol levels, on the order of that of hypercholesterolemic humans. The protective effect of P-selectin deficiency in Apo E ⫺/⫺ mice appeared to be more pronounced and long lasting than was the case in LDLR ⫺/⫺
mice (132). Even at 4 mo of age the size of fibrous plaque
lesions in P-selectin ⫺/⫺, Apo E ⫺/⫺ mice was one-fourth
of that of Apo E ⫺/⫺ mice having wild-type P-selectin.
Hartwell and Wagner (205) emphasize the critical role of
monocytes in atherogenesis suggested by these findings.
Thus the studies on Apo E deficiency mice indicate
that P-selectin/VCAM-1-dependent leukocyte rolling is a
mandatory step in the early development of atherosclerotic lesions. Further evidence to this end was obtained
ex vivo using an isolated carotid artery preparation from
10- to 12-wk-old Apo E ⫺/⫺ and C57BL16 wild-type mice
fed a Western-type diet (21% fat wt/wt) for 4 –5 wk (424).
Adherence and rolling of cells of the mononuclear U937
line on this surface were significantly impaired when
P-selectin or its ligand P-selectin glycoprotein-1 ligand
(PSGL-1) were blocked using specific antibodies. It was
also shown that rolling velocities increased, corresponding to a weaker adhesion, when ␣4-integrin or VCAM-1 of
the mononuclear cells had been blocked using specific
antibodies. This was interpreted as evidence that the
interaction between ␣4-integrin and VCAM-1 has a stabilizing effect on rolling interaction, prolonging the monocyte transit time.
In another study it was shown that endothelin-1 (ET1), which is a potent vasoconstrictor and postulated to
play a role in hypertension (502), ischemia-reperfusion
injury (404), and atherosclerosis (148), can directly promote significant leukocyte adherence and rolling in a
P-selectin-dependent reaction (453).
1073
1074
TABLE
BJARNE ØSTERUD AND EIRIK BJØRKLID
1. Adhesion molecules and ligands known to play a role in atherogenesis
Adhesion Molecule/Other Common Names
Ligand
Integrin
Target Cells
Reference Nos.
P-selectin
GMP-140, PADGEM
CD62P
PSGL-1
CD162
Monocytes, PMN
228
345
578
E-selectin
ELAM-1, LECAM-2
CD62E
PSGL-1
CD162
Monocytes, PMN
133
345
335
L-selectin
LAM-1, LECAM-1, Leu8, MEL-14, TQ-1
CD62L
CD34, glycam-1, MAdCAM-1
Activated EC, lymphocytes,
platelets
228
ICAM-1
CD54 (226)
CD11a/CD18 (LFA-1)
CD11b/CD18 (Mac-1, CR3)
CD11a, ␣L
CD11b, ␣M
CD18, ␤2
Monocytes, PMN,
lymphocytes
133
310
17
VCAM-1
CD106
VLA-4
␣-4
CD49d
␣4␤1, ␣4␤7
Monocytes, PMN
133
401
310
PECAM-1
CD31
PECAM-1
Heparan sulfate
Glycosaminoglycan chains
␣v/␤3-Integrin
248
303, 588
352, 374
ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; VLA-4, very late antigen-4; LFA-1, lymphocyte function
antigen-1; IAP, integrin-associated protein; PECAM, platelet endothelial cell adhesion molecule; PMN, polymorphonuclear cells; EC, endothelial
cells.
1. MCP-1
Chemokines or chemotactic cytokines belong to an
expanding family of structurally related small protein
molecules, allocated to subgroups (C, CC, CXC, CX3C)
according to the number of and spacing of cysteine
residues in the NH2-terminal region. They are critically
involved in directing leukocyte trafficking and activation. MCP-1 emerges as probably having some subordinate role in relation to atherosclerosis. Thus high expression of MCP-1 was found in human atherosclerotic
lesions (428). Transgenic mice overexpressing MCP-1
had threefold increased oxidized lipid and revealed
increased immunostaining for macrophage cell surface
markers unique for the activated state (6). It was concluded that MCP-1 expression mediates enhanced
atherogenesis, by increasing macrophage numbers as
well as accumulation of oxidized lipid. Corroborative
evidence for this notion was found using transgenic
C57BL/6 mice deficient in apolipoprotein apo (a). When
fed a high-fat diet these mice overexpressed MCP-1 and
in a correlating manner macrophages accumulated in
their vasculature (431). Correspondingly, when subjecting LDLR-deficient mice to a high-cholesterol diet, the
ensuing hypercholesterolemia rapidly triggered MCP-1
expression in resident macrophages. Additional numbers of macrophages expressing MCP-1 accumulated
over time, indicating that MCP-1 may initiate as well as
amplify monocyte recruitment to the artery wall during
early atherogenesis (272). This is consistent with the
Physiol Rev • VOL
50% reduction in lesion formation found in MCP-1deficient mice relative to wild type (181). Recently, it
was shown that MCP-1 induces proliferation and IL-6
production in human smooth muscle cells by differential activation of nuclear factor ␬B (NF␬B) and activator protein-1 (AP-1), which may suggest that some hitherto unrecognized mechanism may be involved in the
proatherogenic effect of MCP-1 (542). However, overexpression of MCP-1 at the vessel wall was not sufficient to generate lesion formation in rabbits fed normal
Chow, whereas such overexpression under hypercholesterolemic conditions induced infiltration of monocytes/
macrophages and subsequent lesion formation in the vessel wall (366). On the other hand, hypercholesterolemia
by itself did not cause lesion formation in rabbits with
normal MCP-1 despite upregulation of VCAM-1 and
ICAM-1. It was concluded that activation of other factors
induced by hypercholesterolemia is required.
2. MCP-1 receptors
The function of MCP-1 is totally dependent on its
receptors. In monocytes three different receptors, CCR1,
CCR2, and CCR5, have been identified, the former two of
which were the only ones present in granulocytes (for a
review, see Refs. 56, 241, 428). It has been proposed that
CCR2 serves as the principal MCP-1 receptor. It is upregulated by cytokines and by LDL (202). Mice deficient in Apo
E as well as CCR2 (ApoE ⫺/⫺,CCR2 ⫺/⫺) showed a 50%
reduction in macrophage recruitment compared with wild
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
Monocytes, PMN, EC,
lymphocytes
MONOCYTES IN ATHEROGENESIS
type after 5 wk on a Western diet (62, 110). Currently very
little is known pertaining to the other receptors for MCP-1
and their relative contribution to monocyte recruitment.
3. Factors affecting the production of MCP-1 and other
chemoattractants
Physiol Rev • VOL
cross-talk between T cells and macrophages, effectively
promoting migration of macrophages more closely to the
inflammatory scene.
Macrophages are the richest source of chemokines in
atherosclerotic lesions (13, 45, 373, 429, 515, 550, 582).
When monocytes are stimulated by the vast array of agonists present at the site of foam cell formation, they too
start producing chemokines. The agonists comprise inflammatory cytokines, such as TNF, IL-1␤, IL-6, IL-2, etc.,
produced by macrophages and T cells (304, 327), and
modified LDL particles (105, 265, 511, 519). Thrombinactivated platelets induce the expression of chemokines
MCP-1 and IL-8 in monocytes (559).
IV. ROLE OF LOW-DENSITY LIPOPROTEIN
A. Early, Low-Grade Events
Cholesterol is transported in the circulation by
plasma lipoproteins. The principal cholesterol carrier LDL
serves as an exogeneous source of cholesterol and other
cellular nutrients for hepatic and various extrahepatic
tissues, where it is taken up by receptor-mediated endocytosis. Alternatively, LDL may be entrapped extracellularly in arteries, thus being subjected to a milieu conducive to various kinds of enzymatic and chemical modification. Early stages of arterial lipoprotein modification,
marked by the generation of bioactive lipid peroxidative
products, may occur without any apparent change in
cellular receptor recognition of the particles.
Monocyte-derived macrophages in arteries express
cell surface receptors for LDL (LDL-R) as well as scavenger receptors for modified LDL (SR-A, CD36, CD68) (Table 2). Although minimally oxidized LDL particles appear
physically indistinguishable from native plasma LDL, they
bear a cargo of bioactive molecules. The latter have been
shown to cause a 60% increase in arachidonic acid and a
100% increase in 12 (S-HETE) release from EC, associated
with induced binding of monocytes to EC (219).
Several studies have established that minimally modified LDL (MM-LDL) produces a distinct pattern of EC
activation (47, 256, 394). Transcriptional activation of the
macrophage-colony stimulating gene by MM-LDL was
shown to be mediated by NF␬B activation (423). This was
further confirmed in a study assessing responses to MMLDL by examining the expression of inflammatory genes
involved in atherogenesis, including MCP-1 and MCSF,
and the oxidative stress gene, heme oxygenase-1 (HO-1)
(478). Furthermore, studies on EC isolated from the aorta
of inbred mice with different susceptibilities to diet-induced atherosclerosis revealed that EC from the susceptible mouse strain C57BL/6J exhibited dramatic transcriptional induction of the inflammatory genes, whereas EC
from the resistant strain showed little or no such induc-
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
Adhesion molecules that tether circulating leukocytes to endothelial cells may also serve as transducers or
modulators of incoming signals of cellular activation. Pselectin upregulates the secretion of MCP-1 and TNF-␣
from monocytes stimulated with PAF (560). Furthermore,
IL-8 and MCP-1 were induced in monocytes by thrombinactivated platelets exposing P-selectin (559). IL-8 is produced both in monocytes and granulocytes and has been
thought to act predominantly on neutrophils. However,
recently it was found that it brought on firm adhesion of
rolling monocytes onto monolayers expressing E-selectin,
in the same manner as did MCP-1 (175), a faculty not
shared by related chemokines. The production of IL-8 in
leukocytes is upregulated by epinephrine-stimulated
platelets (142). The prevailing perception of IL-8 as rather
peripherally involved in atherogenesis may have to be
corrected in view of these later findings. It could turn out
more important for proinflammatory reactions and
atherogenesis than anticipated, perhaps via some unexpected role in monocyte recruitment.
Monocyte-derived macrophages in the intima of the
vessel wall generate MCP-1 and other chemoattractants
important for the transendothelial migration of monocytes to the intima. Lysophosphatidylcholine (lysoPC)
formed by the oxidation of LDL particles is a potent
chemoattractant (87, 356, 361, 420), potentially enhancing
the extravasation process. Moreover, since lysoPC serves
to upregulate a series of proinflammatory products in
monocytes/macrophages, it could have an impact on
proinflammatory reactions taking place in a vessel wall
accumulating oxidized LDL (87, 356, 361).
Although it has been proposed that MCP-1 serves as
a principal chemokine directing monocyte infiltration (45,
373, 515, 563, 582), it may be anticipated that this role is
shared somehow with the several other chemokines expressed in atherosclerotic plaques. Prominent among the
latter are the chemoattractants for monocytes, MIP-1␣,
MIP-1␤, and RANTES (regulated upon activation, normal
T-cell expressed) (532). Their common receptor CCR5 is
progressively expressed during monocyte differentiation
(531). Hence, in contrast to CCR2, the main function of
which is in the recruitment of monocytes from the peripheral blood, CCR5 and its ligands appear to have their main
role in affecting macrophages already established within
the lesions (for a review, see Ref. 428). MIP-1␣ and -1␤
colocalize in atherosclerotic plaques (563) and are expressed by T cells in macrophage/foam cell-rich areas of
the plaque. This may be signifying chemokine-mediated
1075
1076
TABLE
BJARNE ØSTERUD AND EIRIK BJØRKLID
2. Macrophage and endothelium scavenger receptors that bind lipoproteins
Receptors
Ligand
Expressing Cells
Scavenger receptor class A, type I
and II (SR-AI/II)
CD36
Oxidized LDL, Ac-LDL, long-chain fatty
acids
Oxidized LDL, long-chain fatty acids
CD68 (macrosialin in mice)
Oxidized LDL
Scavenger receptor class B, type I
(SR-BI)
Lectin-like ox-LDL receptor-1
(LOX-1)
SREC
SR-PSOX
Macrophages, SMC
Reference Nos.
115, 448, 509
363
HDL
Macrophages, monocytes,
platelets, SMC
Macrophages, neutrophils, mast
cells
Macrophages, epithelial cells
Oxidized LDL
Macrophages, SMC
278
Ac-LDL
Oxidized LDL
EC
Macrophages
3
218
425
529
tion (478). Altogether this suggests that genetic factors of
the vessel wall are of importance in atherogenesis.
Lysosphosphatidic acid (LPA) has been identified as
a bioactive compound formed in mildly oxidized LDL and
minimally modified LDL. Thus LPA initiated platelet activation and stimulated endothelial stress-fiber and gap formation (482). LPA receptor antagonists prevented platelet
and endothelial cell activation by mildly oxidized LDL.
Evidence from human surgical and autopsy material
as well as from experimental animal specimens indicates
that monocyte and T-lymphocyte adherence is preceded
by the deposition of lipids underneath the endothelial
cells (14). The flux of LDL into the intima is determined
mainly by the LDL concentration in plasma. LDL enters
the intima and inner media primarily from the luminal
side, passing structures such as the endothelium and the
subendothelial basement membrane. Under normal conditions these structures are the major barriers for the
entry of any kind of plasma macromolecule into the the
inner media (217, 400, 466). The transport of LDL into the
intima is probably not dependent on any specific EC
receptors. Penetration of intact LDL particles into the
arterial wall may occur by vesicular ferrying through the
endothelium or by passive sieving through pores in or
between endothelial cells. Ongoing monocyte trafficking
has been suggested to somehow enhance the transport of
LDL from plasma to the intima (for a review, see Ref. 375).
B. Modulation of LDL
The spherical LDL particle has a cholesteryl esterrich core and a surface dominated by free cholesterol,
phospholipids, and apolipoprotein B100, the normal ligand for the LDL receptor. It is anticipated that under
most circumstances LDL circulating in plasma is protected from oxidation by the presence of antioxidants. In
contrast, the less protective milieu of the arterial wall
renders the particle significantly more vulnerable and
subject to oxidation.
Physiol Rev • VOL
Modification of LDL via oxidative processes is believed to be a prerequisite for the development of atherosclerosis. Oxidation of the particle in the arterial wall is
thought to be a complex reaction involving several cell
types, including monocytes, macrophages, granulocytes,
lymphocytes, endothelial cells, and SMC. Typically oxidation may take place in microenvironments that are exhausted in antioxidants such as vitamin E, carotenoids,
ubiquinol, etc. (146). The importance of LDL oxidation in
lesion formation was recently documented in ApoE-deficient mice consuming red wine for 2 mo (23) with a
subsequent 40% reduction in basal LDL oxidation, and a
similar decrement in LDL oxidizability and aggregation
associated with a 35% reduction in lesion size. The resistance to oxidation was associated with an accumulation
of flavonoids in the mouse macrophages whereby their
capacity to oxidize LDL was reduced and they took up
about 40% less LDL than macrophages from placebotreated mice.
Polyunsaturated fatty acids present in LDL are oxidatively converted to lipid hydroperoxides, which are
subsequently cleaved forming reactive aldehydes. The latter may covalently modify apolipoprotein B100 by forming Schiff’s bases with exposed lysine amino groups, thus
masking the positive charge and in effect increasing the
net negative particle charge, rendering the particles recognizable by macrophage scavenger receptors and subject to unrestrained accumulation by these cells.
Details of the oxidation process have been deduced
mainly from the results of numerous in vitro studies.
Several different reactive oxygen species including superoxide, hydrogen peroxide, hypochlorus acid, hydroxyl
radicals, and peroxynitrite have been implicated in the
initiation of lipid oxidation and peroxidation. Recently, it
was shown that macrophage NAPDH oxidase, the principal vehicle for generating reactive oxygen species (ROS),
does not contribute critically to the development of atherosclerosis (258), a somewhat surprising notion considering the likely exposure to many different ROS of the
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
LDL, low-density lipoprotein; SMC, smooth muscle cells; EC, endothelial cells.
MONOCYTES IN ATHEROGENESIS
C. Proinflammatory Reactions Associated With
LDL Oxidation
Although granulocytes are generally more prolific
than monocytes/macrophages in generating oxidizing
products, i.e., oxygen radicals essential in the defense
system, it appears that also monocytes/macrophages contribute significantly to LDL oxidation. Furthermore, Thelper lymphocytes, generators of IL-4 and IL-13, have
been shown to enhance LDL oxidation mediated by activated monocytes in a 15-lipoxygenase (15-LO)-dependent
fashion (155). Studies using 12-LO and 15-LO knock-out
mice have affirmed the importance of the lipoxygenase
pathway. Thus mice with a combination of ApoE ⫺/⫺ and
12- or 15-LO ⫺/⫺ traits were significantly less prone to
lesion formation than were wild-type animals (107). When
a specific inhibitor of 15-LO, PD 14167, was administered
in a rabbit experimental model, atherosclerotic lesions
had reduced monocyte/macrophage numbers, and fibrofoamy and fibrous plaque lesion development was diminished (53).
1. Impact of oxLDL
Once modified (e.g., oxidized or acylated) and taken
up by macrophages, LDL activates the nascent foam cell.
Modified LDL is chemotactic for monocytes and can upPhysiol Rev • VOL
regulate the expression of genes for macrophage colony
stimulating factor (419, 422) and MCP-1 (293) (Fig. 1).
Thus oxLDL may help expand the inflammatory response
by stimulating the replication of monocyte-derived macrophages and the entry of new monocytes into lesions.
Effects attributed to oxLDL pertaining to macrophage
function include proinflammatory effects, such as increased proliferation (199, 330, 333, 450) and expression
of inflammatory cytokines (222, 408), toxicity (300), increased expression of metalloproteinases (223), inhibited
expression of inducible nitric oxide synthase (223), and
effects on macrophage lipid metabolism and accumulation (179, 243, 500, 551). Released inflammatory mediators like IL-1␤, TNF-␣, and MCSF enhance the binding of
LDL to the endothelium and smooth muscle and increase
the transcription of the LDLR gene (196, 503), thereby
having an impact on the migratory pattern of LDL within
the artery. Upon binding of modified LDL to scavenger
receptors in vitro, various intracellular events are initiated, including the induction of IL-1␤ (170, 391, 392) and
urokinase (147). Thus, given the generation of sufficient
amounts of modified lipids and a progressing inflammation, unless there is some tip of the balance, atherosclerosis development is sustained by the mutual reinforcement of these processes.
V. MONOCYTE DIFFERENTIATION AND THE
ROLE OF THE EXTRACELLULAR MATRIX
IN ATHEROGENESIS
A. Macrophage Formation
When circulating peripheral monocytes migrate from
the vascular to the extravascular compartment, a process
entailing maturation of the cells to macrophages is concomitantly launched. This differentiation process renders
the cells ready for active participation in the inflammatory
and immune responses. The process has been shown to
depend on many transcription factors, and a novel role for
NF␬B has been suggested due to its accumulation in the
cytoplasm of cells differentiated into macrophages (514).
Part of the arsenal of the differentiated cells is an acquired acute responsiveness to, e.g., LPS, and enhanced
capacity for TNF-␣ secretion.
Comparatively little is known about the functional
properties of macrophages in vivo, but on average their
overall reactivity appears to be substantially higher than
that of circulating monocytes. Thus, although oxidized
LDL may fail to induce monocyte activation in whole
blood (65), an altogether different situation prevails in the
intima, where a whole series of activation products may
be anticipated after interaction of macrophages with oxidized LDL.
Macrophages are key players in many aspects of
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
lipoproteins abundantly accumulating at atherosclerotic
sites. The finding is evidence for the presence of alternative systems contributing critically to lipoprotein oxidation. Prime candidates are the lipoxygenase enzymes (described later) catalyzing lipid alkoxyl radical (LOO⫺) formation from esterified fatty acids. Such lipid peroxidation
may bypass the generation of superoxide or any of its
derived reactive products.
Although the mechanisms by which lipoproteins are
oxidized in vivo are still debated, some of the products
present in minimally modified/oxidized LDL (MM-LDL)
have been identified, including 1-palmitoyl-2- (5,6)-epoxyisoprostane E2 (PEIPC), 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine (PGPC), and 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine (POVPC), principal inflammatory mediators of reactions promoting
atherogenesis. These phospholipid oxidation products are
prominent in atherosclerotic lesions. Moreover, they have
been shown to mediate the activation of monocytes
and/or endothelial cells in vitro in the presence of PAF
(290, 505). The administration of WEB 2086, a PAF analog
and selective PAF receptor antagonist, to C57BL/6J LDLR
⫺/⫺ mice fed a Western diet, reduced the fatty streak
formation by 62% (505). Altogether, these studies favor
the notion of important roles for PAF and/or PAF-like
phospholipid oxidation products in mediating atherosclerotic lesion development.
1077
1078
BJARNE ØSTERUD AND EIRIK BJØRKLID
human physiology and disease. A whole spectrum of macrophage subpopulations with distinct and often uncharted
functions may be formed, as directed by the microenvironments of the differentiating monocytes. Current
Physiol Rev • VOL
knowledge about monocyte differentiation has largely
been derived from in vitro studies, many aspects of which
may not truly reflect the activation reactions associated
with differentiation in vivo. Nevertheless, the upregula-
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
FIG. 1. Foam cell formation in the intima. Low-density lipoprotein (LDL) can pass into and out of the intima,
but when present in excess it tends to be trapped in the matrix by binding to proteoglycans. At limiting levels of
antioxidants, the lipids and proteins of LDL are subject to oxidation by oxidating products derived from cells
residing in the vessel wall, the LDL proteins being subject also to glycation processes. Thus arises minimally
modified LDL (MM-LDL), which upon further oxidation eventually becomes oxidized LDL. Recruitment of mononuclear cells (monocytes and T lymphocytes) as a specialized inflammatory response to modified LDL exposure
characterizes the initiation phase of atherosclerotic lesion formation. Specific adhesion molecules such as von
Willebrand factor, the selectins, and vascular cell adhesion molecule (VCAM)-1, expressed on the surface of
activated vascular endothelial cells, mediate leukocyte adhesion. Once adherent, the mononuclear cells enter the
artery wall directed by chemoattractant chemokines such as monocyte chemoattractant protein-1 (MCP-1). LDL
particles trapped in the intima are prone to progressing oxidation, rendering them recognizable by macrophage
scavenger receptors and thus targets for internalization by these cells. Upon extensive uptake of modified LDL via
scavenger receptors (CD36 and SR-A), macrophages are ultimately turned into foam cells. This differentiation
process may be accelerated by macrophage colony stimulating factor (MCSF), lipopolysaccharide (LPS) via the
receptor CD14 in conjunction with toll-like receptor 4 (TLR4), by heat shock protein (HSP-60) via CD14, and by
platelet activating factor (PAF) and cytokines released from macrophages in an autocrine loop. Peroxisome
proliferator-activated receptor-␥ (PPAR␥) is activated by LDL lipids, leading to upregulation of CD36 and downregulation of cytokine release. In the process of foam cell formation, cytokines released from macrophages and T
lymphocytes are acting in concert on foam cells and on smooth muscle cells and endothelial cells (EC). T-cell
mobilization and activation leads to secretion of the cytokine interferon-␥ (IFN-␥), which primes the macrophages
rendering them more susceptible to TLR-dependent activation. Activated T cells also express CD40 ligand (CD40L),
which ligates its receptor CD40 on macrophages. Chemoattractants released from LDL, macrophages, and foam
cells (MCP-1) promote further monocyte recruitment to the intima. Although the focus of this review is the role of
monocytes/macrophages in the early phase of atherogenesis, it should be stressed that the accumulation of oxidized
LDL in the intima and the resultant cellular activation products like chemoattractants, growth factors, and cytokines
also promote smooth muscle cell proliferation, uptake of oxidized LDL, and eventually conversion to lipid-laden
foam cells. Foam cells derived from smooth muscle cells together with those derived from macrophages generate
the fatty lesion.
MONOCYTES IN ATHEROGENESIS
B. Foam Cell Formation
A hallmark of the development of atherosclerotic
plaques is the prior and concurrent acccumulation in the
arterial intima of lipoprotein particles subject to chemical
modifications. This is associated with local inflammation
in the vessel wall and further recruitment of monocytes
from the circulation. By taking up such modified LDL
(oxidized or acetylated), monocyte-derived macrophages
are turned into fat-loaded macrophages residing in the
vessel wall and furthering the local inflammatory response. The mechanisms underlying such foam cell generation has for several years been the focus of intensive
research (46, 72, 90, 499, 568) (Fig. 1).
Macrophages are normally protected from the accumulation of toxic cholesterol loads by multiple mechanisms, notably the downregulation of surface LDL receptor molecules in response to replete intracellular cholesterol stores (72). However, oxidized or otherwise
chemically modified LDL may be taken up by alternate
“scavenger” or “oxidized LDL” receptors that are not similarly downregulated when the cholesterol load is in excess (46, 90, 499, 568), thereby evading regular homeostatic control mechanisms. A series of scavenger receptors have been identified and are listed in Table 2. These
comprise several classes of transmembrane receptors, a
common characteristic of which is an affinity for negatively charged macromolecules or particles like, e.g.,
modified LDL.
An important role of the SR-A receptor in atherogenesis was inferred from the first analysis of mice with a
Physiol Rev • VOL
combined SR-A and ApoE deficiency. These mice had a
60% reduction in atherosclerotic lesion development compared with wild type (509). However, more recent studies
have been less affirmative of such a proatherogenic role
for SR-A. Thus a combined SR-A and LDL-R deficiency
caused only 20% reduction in atherosclerosis (448). Furthermore, when subjecting apoEJ-Leiden mice (another
proatherogenic mouse model) to the added deficiency of
SR-A, no decrease in atherosclerosis was observed (118).
This controversy has been interpreted as an indication
that ApoE has a complex role in pathogenesis, related to
the fact that ApoE not only acts in plasma lipoprotein
metabolism, but it also has a stimulatory influence on the
efflux of cholesterol from macrophages (209, 280). One
would anticipate the latter effect to serve as a protective
mechanism counteracting foam cell formation.
Recently, more solid support for a central role of the
class B scavenger receptor CD36 was provided by the
demonstration that crosses of ApoE deficiency mice with
CD36 deficiency mice had a 76% reduction in lesion area
compared with mice deficient in ApoE only, after 12 wk
on a Western diet (150). CD36 has been identified as the
receptor facilitating myeloperoxidase-modified (MPOmodified) LDL uptake. MPO-modified LDL has a proven
capacity to induce foam cell formation in vitro and is
likely to be highly proatherogenic. CD36 deficiency in
mice reduced the uptake of MPO-modified LDL by almost
90% and the formation of foam cells by ⬎50% (412). It has
to be borne in mind, however, that one cannot automatically infer from this marker role of CD36 in knock-out
mouse models, that it has a corresponding role in human
pathophysiology. Several other scavenger receptors have
also been shown to be important for the uptake of oxidized LDL and the pathogenesis of atherosclerosis (see
Table 2). Among these scavengers are macrosialin/CD68,
lectinlike oxidized LDL receptor (LOX-1) and SREC (for
review, see Ref. 120).
The results emerging from transgenic mouse models
should be interpreted with caution, considering such factors as control of genetic background, linkage problems,
etc. Furthermore, to better mimic the human situation,
more refined heterozygotic models assessing various
markers and polymorphisms, alone or in combination,
may be called for (for a review, see Ref. 266).
The prominent role of modified LDL in atherogenesis
suggests that addressing the undesirable proliferation or
action of LDL-related products might have considerable
prophylactic or even curative potential. Conceivably the
following approaches might prove useful: saturation with
relevant antioxidants to prevent LDL oxidation, directly at
the level of the particle itself or indirectly at the level of
the cellular oxidative machinery, or conversion of already
oxidized LDL to a nonatherogenic particle using HDLassociated paroxonase (PON-1) (249).
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
tion as well as downregulation of certain receptors is well
documented. Thus alveolar macrophages showed much
lower expression of ␣4-, ␣6-, and ␤2-integrins, CD11a,
CD11b, L-selectin, Le (x), and sialyl Le (x) compared with
monocytes (416). In one in vitro study it was shown that all
adherent monocytes expressed CD14, CD36, and LDLR. In
tissue macrophages these antigens were less consistently
expressed and defined three cellular subpopulations:
CD36⫹CD14⫺LDLR⫺ (58 ⫾ 12%), CD36⫹CD14⫹LDLR⫹
(18 ⫾ 5%), and CD36⫺CD14⫺LDLR⫺ (remaining cells)
(567). Thus CD36 appeared to be present in three-fourths of
the macrophages, a significant fraction considering the central role of CD36 as an oxLDL scavenger receptor. Another
marker that is also induced during monocyte to macrophage
differentiation is the class A macrophage scavenger receptor
(SR-A). This protein mediated 80% of the uptake of acetylated LDL by human monocyte-derived macrophages (182).
The upregulation of platelet-derived growth factor (PDGF)
receptors on human monocyte-derived macrophages has
been taken as evidence that PDGF has a role in atherogenesis, regulating the function of macrophages as well as SMC
in the vascular wall (232).
1079
1080
BJARNE ØSTERUD AND EIRIK BJØRKLID
molecules controlling their activation and by specific inhibitors known as the tissue inhibitors of metalloproteinases (TIMPs) (149).
C. Roles of Extracellular Matrix and
Metalloproteinases in Atherogenesis
Physiol Rev • VOL
VI. MONOCYTES/MACROPHAGES AND THE
ROLE OF THEIR ACTIVATION PRODUCTS
A. Regulation of Activation
Monocytes play a central role under several pathophysiological conditions, particularly when the progression of the disease stems from underlying inflammatory
reactions, e.g., in diseases like rheumatoid arthritis, atherosclerosis, psoriasis, asthma, and inflammatory bowel
disease. The proinflammatory potential of the monocytes
can only be unlocked by their activation/differentiation
and subsequent secretion of activation products, the main
classes of which are summarized in Table 3. More than
100 different biologically active molecules are known to
be secreted by monocytes/macrophages.
Monocytes are activated only according to what is
dictated by their particular environment, notably by its
content of agonists including primers. The various monocyte agonists associated with monocyte/macrophage activation during atherogenesis are listed in Table 4 according to their type or the group to which they belong. Most
of these substances have so far been reported to have
agonist properties in relation to monocytes, i.e., activa-
TABLE 3. Biological products of monocytes
and macrophages
Complement factors (produce all essential components of the
complement system) (94)
Coagulation factors (the vitamin K-dependent FVII, FX, FV,
prothrombin, fibrinogen and tissue factor: all factors needed to
generate fibrin) (384, 386)
Prostaglandins (see review, Ref. 368)
Leukotrienes (451)
Growth factors [PDGF (211), TGF-␤ (547), MCSF and GCSF (75)]
Cytokines (TNF, IL-1␤, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, IL-18,
IFN-␥) (78)
PAF (117), lyso-PC (420)
Chemokines (MCP-1,-2,-3, IL-8, RANTES, ELC, PARC, MIP-1␣,␤,
eotaxin, MDC, TARC, LARC) (for review, see Ref. 27)
Oxygen radicals (42, 96)
Proteolytic enzymes (e.g., elastase, cathepsin G, metalloproteinases)
(474)
PDGF, platelet-derived growth factor; TGF-␤, transforming growth
factor ␤; MCSF, monocyte/macrophage colony stimulating factor; GCSF,
granulocyte colony stimulating factors; PAF, platelet activating factor;
lyso-PC, lysophosphatidylcholine; MCP, monocyte chemoattractant protein; RANTES, regulated upon activation, normal T-cell expressed; ELC,
EBI1-ligand chemokine; PARC, pulmonary and activation regulated chemokine; MIP, macrophage inflammatory protein; MDC, macrophagederived chemokine; TARC, thymus and activation-regulated chemokine;
LARC, liver and activation-regulated chemokine; IL, interleukin; IFN,
interferon; TNF, tumor necrosis factor.
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
Monocytes migrating into the subendothelial space
probably interact with ECM components, notably collagen type I, a major constituent of the normal arterial wall
(495), and the most prominent matrix component of atherosclerotic plaques (496). Strong interaction between
monocytes and matrix is proabably a prerequisite for the
formation of lipid-laden macrophages, since lipid does not
accumulate in monocytes that do not form stable interactions with tissues, even if they are allowed to differentiate
into macrophages (558).
The ECM molecules are synthesized by resident cells
of vascular tissue, such as endothelial cells, macrophages,
and smooth muscle cells. Atherogenic lipoproteins gaining access to the subendothelial space are bound and
retained through ionic interactions between positively
charged residues on their apolipoproteins (apo B and
apoE), and negatively charged sulfate and carboxylic acid
residues on the glycosaminoglycan chains of extravascular or cell-associated vascular proteoglycans (for review,
see Ref. 84). One of the tenets of the response to retention
hypothesis is that prolonged residence time of lipoproteins in the intima leads to lipoprotein modification.
Recently, it was shown that oxidized LDL particles
retained by ECM proteoglycans were taken up by macrophages, provided the ECM had been preincubated with
lipoprotein lipase before adding ox-LDL (250).
Matrix metalloproteinases (MMP) are a family of enzymes comprising at least 16 zinc-dependent endopeptidases that are catalytically active against ECM components (for review, see Ref. 174). They are essential for
cellular migration and tissue remodeling under both physiological and pathophysiological conditions (359). In vitro
studies have demonstrated that the expression of MMP-1,
MMP-3, and MMP-9 in macrophages and smooth muscle
cells is enhanced by several mediators secreted from T
lymphocytes and monocytes, e.g., TNF-␣ and IL-1␤ (165,
282), whilst it is suppressed by the general inhibitors of
monocyte activation IL-4, INF-␥, and IL-10. The activities
of matrix-degrading MMP are essential for many of the
processes involved in atherosclerotic plaque formation,
including infiltration of inflammatory cells as outlined
above, SMC migration, and proliferation as well as angiogenesis. Probably the most serious consequences of MMP
activities are the unfavorable effects on plaque stability
and resistance to rupture, which may lead to unstable
angina, myocardial infarction, and stroke (166).
MMP need to be activated, and urokinase (produced
by macrophages) and the plasminogen system are known
to play central roles in the processes where MMP are
important (102). MMP are in fact tightly regulated by
MONOCYTES IN ATHEROGENESIS
TABLE 4. Agents that induce or enhance
monocyte/macrophage activation and that have been
associated with the development of atherosclerosis
tion is induced/primed by their presence. However, the
interpretation of these data has been complicated by the
fact that certain poorly charted and hard to avoid lowgrade monocyte activation phenomena may be inherent in
the isolation and culturing processes per se. Prime suspected culprits are mechanical stress and trace contaminants going undetected or not even looked for in the
system, the outcome being already preactivated and/or
primed cells, quite commonly not acknowledged as such.
Indeed, when monocytes adhere to plastic or to extracellular matrix proteins, signals are delivered that induce
expression of immediate-early (IE) response genes (246).
While mRNA accumulates in these adherent monocytes,
the cytokine expression products including IL-1␤ and
TNF-␣ are not secreted unless there is a “second stimulus” such as bacterial LPS (206).
In contrast, in the native environment of whole blood
ex vivo, LPS appears to be the sole monocyte activator.
Cytokines, growth factors, adhesion molecules, etc., reported as stimulants or agonists in cell culture studies,
may in the native environment of whole blood only upregulate ongoing activation (383). Thus activation effects
assigned to particular agonists cannot be seen in isolation
from the overall experimental setting, and the relevance
for the in vivo situation should be interpreted with caution.
Many of the products generated by activated monocytes/macrophages require similar transcription factors
Physiol Rev • VOL
for their synthesis. Thus active nuclear factors NF␬B and
AP-1 are mandatory for the production of cytokines, tissue factor, and growth factors, strongly suggesting that
they are crucial for monocyte reactivity (Fig. 2) (122).
Evidence to support this hypothesis has been obtained
from in vivo studies using a mouse strain subjected to an
atherogenic diet. The susceptibility to aortic atherosclerotic lesion formation turned out to be associated with
accumulation of lipid peroxidation products, induction of
inflammatory genes, and the activation of NF␬B-like transcription factors (301).
Further evidence that NF␬B-dependent gene transcription has a role in atherosclerosis was obtained by
subjecting C57B16 mice to intravenous administration of
mildly oxidized LDL. This led to induced expression in the
liver of the same set of genes as when the mice were fed
an atherogenic diet. An inbred strain of these mice susceptible to fatty streak formation was shown to have
particularly profuse expression in liver of genes associated with inflammation, and this trait cosegregated with a
propensity for activation of a NF␬B-like transcription factor and with the level of oxidized lipids in the same organ
(302).
Most of the products listed in Table 4 are probably
more effective in activating monocyte-derived macrophages in the intima than they are in activating monocytes. In relation to atherogenesis, it has been established
that various cytokines, immunostimulatory agents, as
well as growth factors are potent activators of macrophages (Table 4). Furthermore, platelet-derived activation
products, lipids (e.g., ox-LDL), and certain eicosanoids
have similar effects. Recently, it was also shown that
monocyte activation is upregulated by fibrinogen, indicating a proinflammatory role of this protein (314). Since
physiologically unperturbed macrophages are virtually
impossible to obtain in isolation, it remains difficult to
infer from such studies which of the agonists listed in
Table 4 are playing the most important roles in atherogenesis.
B. Autocrine- and Paracrine-Mediated Activation
Reactions in Monocytes
Autocrine activation (effects of a substance secreted
by a cell on that cell itself) and paracrine activation
(action of substances produced by cells and acting at
short range on neighboring cells) are important regulatory processes of monocyte activation. Probably one of
the most important autocrine activators is TNF-␣, produced in monocytes and known to upregulate the synthesis of cytokines (410) and tissue factor in monocytes
(137). Furthermore, TNF-␣ may induce the production of
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
Immune stimulatory agents
Lipopolysaccharide (190)
Immune complexes (15)
Complement factors C3a and C5a (393)
Lectins (427)
Virus (129)
Growth factors
Platelet-derived growth factor (144, 232)
Monocyte/macrophage colony stimulating factor (145)
Granulocyte colony stimulating factor (52)
Cytokines
IL-1␤, TNF-␣, IL-6, IL-2, IL-8 (78)
Lipids
Oxidized LDL (245)
Lipoproteins (70)
Platelet-derived activation products
P-selectin (for review, see Ref. 162)
Platelet microparticles (36)
Platelet factor 4 (141)
Eicosanoids
Leukotriene B4 (516)
Proteins
Fibrinogen (314)
Proteoglycans (421)
Proteases (364, 573)
Oxygen radicals (for review, see Ref. 40)
1081
1082
BJARNE ØSTERUD AND EIRIK BJØRKLID
IL-1␤ in monocytes, which in turn may promote a series of
inflammatory reactions (273). The autocrine effect of
TNF-␣ is mediated through the activation of NF␬B (77).
The activation product PAF, produced mainly in
granulocytes, has also proven to be a very potent proinflammatory substance and capable of activating monoPhysiol Rev • VOL
cytes (57) or enhancing the expression of monocyte activation products, e.g., tissue factor (TF) (381), the most
potent trigger of thrombin generation. The observation
that PAF antagonism was one of three major routes for
inhibition of LPS-induced monocyte TF and TNF-␣ synthesis in a whole blood system (135) adds to the evidence
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
FIG. 2. Schematic representation of signal transduction mechanisms involved in monocyte/macrophage activation.
The recognition of lipopolysaccharide (LPS) from Gram-negative bacteria is mediated via the three membrane proteins
CD14, MD2, and TLR4. Although CD14 has numerous ligands, TLR4 and MD-2 provide greater specificity for LPS.
Activation of TLR4 triggers several subsequent steps including the recruitment of intracellular scaffold proteins (such as
MyD88, TIRAP, and Tollip), autophosphorylation of IRAK and ubiquitination of TRAF6. Ubiquitination of TRAF6 triggers
its oligomerization and the recruitment and activation of kinase complexes that mediate phosphorylation of the inactive
NF-␬B-I␤ complex, liberation of the transcription factor NF-␬B, the phosphorylation and activation of the mitogenactivated protein kinase (MAPK) pathways. Together these events lead to the transcription of diverse proinflammatory
genes as well as activation of proinflammatory enzymes such as cytosolic phospholipase A2 (cPLA2). Increases in Ca2⫹
levels induce cPLA2 and lipoxygenase translocation from the cytoplasm to the perinuclear region and nuclear envelope,
where arachidonic acid is liberated from membrane phospholipids by cPLA2 and further metabolized to prostaglandins,
thromboxanes, and leukotrienes by cyclooxygenase (COX)-1, COX-2, and lipoxygenases. The downstream signaling
pathways used by the interleukin (IL)-1 receptor and the tumor necrosis factor (TNF) receptor 1 are also depicted.
Inflammatory reactions by heat shock protein and saturated fatty acids are also induced through the TLR4 receptor. AA,
arachidonic acid; CM, cellular membrane; ER, endoplasmic reticulum; FLAP, 5-lipoxygenase activating protein; HETEs,
hydroxyeicosatetraenoic acids; IKK, I␬ B kinase; IL-1R, IL-1 receptor; IRAK, interleukin-1 receptor-associated kinase;
LBP, lipopolysaccharide-binding protein; 5-LO, 5-lipoxygenase; kinase; NF-␬B, nuclear factor-␬B; PLC, phospholipase C;
PPAR, peroxisome proliferator-activated receptor; RIP, receptor-interacting protein; sPLA2, secretory PLA2; TLR4,
toll-like receptor 4; TNFR1, TNF receptor type 1 (55-kDa TNF receptor); TRADD, TNFR1-associated death domain
protein; TRAF 2/6, TNF-associated factor 2/6; TXA2, thromboxane A2.
MONOCYTES IN ATHEROGENESIS
that autocrine/paracrine activation plays a pivotal role in
the activation of monocytes.
C. Roles of Cytokines Produced
by Monocytes/Macrophages
1. TNF-␣
Monocytes and macrophages produce a variety of
cytokines, all of which are important regulators or modulators of inflammation and hence likely to be key players
during atherogenesis. Among these the 17-kDa protein
TNF-␣ has a master-type of role, initiating the release of a
whole cascade of cytokines involved in inflammatory responses. This central role of TNF-␣ has been documented
in studies where rheumatoid arthritis patients (139) and
patients with Crohn’s disease were successfully treated
(493).
Activation of a series of surface receptors, including
CD11a, CD18, CD45, CD44, CD58, and P-selectin, have
been reported to mediate the induction of TNF-␣ in monocytes cultured in vitro (210, 268, 475). However, these
findings are probably highly system dependent and hinging on poorly defined low-grade preactivation events inherent in the isolation and culturing processes to which
the cells are subjected (383).
TNF-␣ exerts many of its effects by binding as a
trimer to either of two membrane receptors, TNFR1 (55
kDa) or TNFR2 (75 kDa) (230) (now named TNFRSF1A
and TNFRSF1B, repectively; Ref. 311). These receptors
both belong to the so-called TNF receptor superfamily.
Other members of this superfamily comprise FAS, CD40,
CD27, and RANK. These receptors are distinct from the
IL-1 and LPS receptors (Fig. 2).
Cell stimulation by TNF-␣ involves the downstream
activation of transcription factor NF␬B, a mechanism central to several agonists, including IL-1␤ and LPS (Fig. 2).
Recent studies have shown that both cytosolic and secretory phospholipase A2 may be involved in the TNF signal
transduction pathway, ultimately leading to nuclear translocation of NF␬B and ensuing activated gene expression
(524).
The primary event of monocyte activation has been
extensively explored, particularly when LPS serves as the
agonist. Taking into account the emerging notion that
chronic infectious diseases may unleash mechanisms that
Physiol Rev • VOL
favor atherogenesis, the cellular signaling events leading
to the systemic inflammatory response to LPS are summarized in Figure 2. In plasma LPS binds to LPS-binding
protein, forming a complex which may then interact with
CD14, a transmembrane domainless receptor on monocytes that by itself is unable to mediate activation of
signal transduction (207). Recently, evidence has
emerged that once formed the LPS-CD14 complex may
bind to a Toll-like receptor (TLR4) serving as the actual
mediator for signaling into the cells via a number of
transductors recruited to the receptor, eventually leading
to NF␬B activation (for details, see Ref. 207). The latter
factor is involved in regulating numerous genes critically
for inflammatory responses, including IL-8, IL-6, VCAM-1,
and E-selectin (113).
The role of TNF-␣ in the early phase of atherogenesis
has been searched for. Surprsingly, it has been shown that
C57BL/6 mice lacking p66 (TNFRSF1A) and fed an atherogenic diet developed significantly larger lesions than did
receptor-positive mice, thus generating larger numbers of
foam cells (461). In contrast, lack of TNF-␣ did not alter
lesion development, whereas loss of lymphotoxin-␣
(LT-␣, a proinflammatory TNF-␣ homologous cytokine
which also elicits responses though the p55 and p75 receptors) was associated with a 62% reduction in lesion
size (462). These findings suggest that TNF-␣ may also be
interacting with cells through receptors different from
p55 and p75.
Other TNF receptor and ligand superfamily members
have been shown to be new players in the emerging
perception of atherogenesis. Thus TNF receptor superfamily 14 has been suggested to be involved in atherogenesis by inducing TNF-␣ and IL-8 as well as the matrix
metalloproteinases MMP-1, MMP-9, MMP-13, and tissue
inhibitors of MMP-1 and MMP-2 (285). Furthermore, TNFRS5 (CD40) has also been implicated in atherosclerosis
and is expressed by EC, SMC, T lymphocytes, and macrophages in lesions (317). Preventing CD40 ligation with
anti CD40L (TNFSF5) antibodies in hyperlipidemic mice
(LDLR ⫺/⫺) reduced the size of developing aortic atherosclerosis lesions (316).
For further details on the variety of biological responses mediated by TNF-␣, the reader is referred to an
excellent review (4).
2. IL-1␤
IL-1␤ in its mature form is a 17-kDa, 159-amino acid
residues protein, with an isoelectric point of 5.5. During
inflammation, transcription of the protein is stimulated by
immune complexes, certain coagulation and complement
proteins, substance P, and viral or bacterial products,
notably LPS (93). It is also induced or enhanced by certain
cytokines of lymphocyte origin, such as the granulocytemacrophage colony stimulating factor (GM-CSF) (485)
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
Leukocyte generation of cytokines plays a pivotal
role in the progression of inflammatory states such as
rheumatoid arthritis, psoriasis, inflammatory bowel diseases, asthma, and also in atherogenesis (444). Unlike
classical hormones, cytokines are produced locally by a
variety of cells widespread throughout the body. In this
review we focus solely on monocyte/macrophage cytokines that may have a role in atherogenesis.
1083
1084
BJARNE ØSTERUD AND EIRIK BJØRKLID
3. IL-4 and IL-13
IL-4 in its mature form is a glycoprotein of 129 amino
acids and is produced by Th2-T lymphocytes and also
secreted by mast cells and NK cells. It is a pleitropic
cytokine acting on T and B lymphocytes, monocytes,
polymorphonuclear cells, fibroblasts, and EC. Its effects
on B cells entail upregulation of MHC class II and Ig class
Physiol Rev • VOL
switching. IL-4 blocks some of the effects of IL-12,
whereas IFN-␥ blocks some of the effects of IL-4 (32). The
effects of IL-4 and IL-13 on human monocytes and endothelial cells are quite similar, since the receptors for these
cytokines share a common predominant receptor signaling chain (IL-4R␣) (204). Thus both enhance the LDL
oxidizing potential of human monocytes, whereas IFN-␥
inhibits the cell-mediated oxidation. The up- and downregulation of activated monocyte-mediated LDL oxidation
correlates with the expression of 15-LO activity (155). In
accordance with this scenario it is suggested that dietary
lectins, which have been shown to trigger IL-4 and IL-13
release from basophils, may play a role in inducing socalled early IL-4 required to switch the immune response
toward a Th2 response and type I allergy (63). The latter
condition is probably mediated by 15-LO (192).
Recently, it was found that IL-4 deficiency decreases
atherosclerotic lesion formation in a site-specific manner
in female LDLR ⫺/⫺ mice (257). IL-4 is generally considered to be an anti-inflammatory cytokine, but several
processes that are regulated by IL-4 could hypothetically
increase lesion formation, including monocyte recruitment (566), monocyte adhesion (34), lipoprotein modification (97, 506), and macrophage metabolism of modified
lipoproteins (99, 579). However, in another study, IL-4
deficiency did not affect early atherosclerosis in C57BL/6
mice fed a high-cholesterol diet (172). The reasons for the
discrepancy between these two studies are unknown.
4. IL-6
IL-6 is a pleiotropic cytokine that has been implicated
in the pathology of many diseases, including atherosclerosis, rheumatoid arthritis (216), multiple myeloma (38,
253), psoriasis (188), Kaposi sarcoma (344), sepsis (545),
and osteoporosis (240). IL-6 belongs to a family of cytokines that includes IL-11, leukemic inhibitor family (LIF),
oncostatin, cardiotropin-1, and ciliary neutrophilic factor
(159, 581) (for a review, see Ref. 484). IL-6 plays a central
role in diverse host defense mechanisms, such as the
general immune response, acute phase reactions, and
hematopoiesis (for reviews, see Refs. 8, 260). IL-6 is also
important for the activation of the coagulation system,
since its elimination attenuated the activation of this system during experimental endotoxinemia in chimpanzees
(538).
The biological activity of IL-6 is mediated via two
membrane receptor proteins, a unique low-affinity binding receptor (IL-6R) and the high-affinity transducing
␤-subunit gp130. gp130 is also a partner in receptor complexes that have LIF, OSM, CNTF, and IL-11 as ligands
(159, 167, 233, 309, 510). The documentation that IL-6
serves as a proatherogenic cytokine remains rather limited. However, infusion of recombinant IL-6 in C57B1/6
mice (ApoE-deficient mice) exacerbates early lesions in
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
and interferon-␥ (IFN-␥). TNF has been reported to stimulate the production of IL-1␤ by monocytes (128), EC
(372), and fibroblasts (281). Similarly, administration of
IL-1␤ and TNF-␣ in vivo induced the generation of detectable circulating levels of IL-1␤ (127).
The IL-1␤ receptor protein is a conserved member of
the TLR family and is located at a site separately from that
of LPS-CD14 (see Fig. 2). NF␬B activation induced via this
receptor is mediated by the same signal transduction
system as that of LPS-CD14, since both pathways converge at the level TRAF6 activation (see Fig. 2). Along
with TNF-␣, IL-1␤ is one of the principal proinflammtory
products generated in monocytes/macrophages. In fact,
IL-1␤ may mimic activation signals typically induced by
TNF-␣. Furthermore, IL-1␤ acts as a chemoattractant for
neutrophils (for review, see Ref. 312), induces release of
neutrophils from the bone marrow into the circulation
(11), and enhances leukocyte adherence to the endothelium. Like IL-6 it stimulates hepatocytes for secretion of
other acute phase proteins. Also, IL-1␤ promotes endothelial cell proliferation and induces T-cell activation
through increased IL-2 production and upregulation of the
IL-2 receptor.
An IL-1 receptor antagonist, attenuating this receptor’s function, is present in circulating blood (313). In a
recent study where transgenic mice (LDLR ⫺/⫺) overexpressing IL-1 receptor antagonist were fed a high-cholesterol/high-fat diet containing cholate, a 40% decrease in
lesion was observed compared with LDLR knock-out
mice lacking the transgene (117). Further evidence for an
important role of IL-1␤ in atherogenesis was provided by
blocking of IL-1␤ in ApoE ⫺/⫺ mice, which impeded the
development of atherosclerosis (136).
The IL-18 cytokine is a member of the IL-1 family, and
its receptor and signal transduction system are analogous
to those of IL-1␤ (7). IL-18 has potent IFN-␥-inducing
activities. It is a proatherogenic cytokine by increasing
lesion development through enhancement of an inflammatory response involving a IFN-␥-dependent mechanism
(561). Thus IL-18, which by itself is generally a weak
stimulator of IFN-␥ release, functions synergistically with
IL-12 to induce pronounced secretion of IFN-␥ production
by T cells, natural killer (NK) cells, and macrophages
(353). Accordingly, it has been shown that administration
of exogenous IL-12 to ApoE ⫺/⫺ mice will promote lesion
development (284).
MONOCYTES IN ATHEROGENESIS
these animals (227). The IL-6 injection was associated
with a rise in IL-6, IL-1␤, TNF-␣, and fibrinogen, whereas
total cholesterol levels were unchanged between recombinant IL-6 (rIL-6)-treated and nontreated group. However, IL-6 may also be regarded as an anti-inflammatory
cytokine as it attenuates the synthesis of proinflammatory
cytokines through the induction of the synthesis of glucocorticoids and furthermore promotes the synthesis of
IL-1 receptor antagonist and release of soluble TNF receptor (inhibitory of TNF function) in human volunteers
(525).
5. IL-12
6. IFN-␥
The cytokine IFN-␥ has an important role in inducing
and modulating a whole array of immune responses. It is
produced by Th1 T lymphocytes and by activated NK
cells. IFN-␥ produced in NK cells is important in acute
inflammation, mainly because of the activating effect it
has on the adhesional properties of the endothelium and
on mediator production by mononuclear phagocytes.
Thus it upregulates the expression of endothelial ICAM-1
and of monocyte IL-1, PAF, and H2O2. INF-␥ has a suppressive effect on IL-8 expression but upregulates the
production of LPS-induced NO as well as IL-12 in monocytes (for reviews, see Refs. 49, 517).
IFN-␥ has been suggested to play a central role in
atherogenesis. IFN-␥ was shown to promote atherosclerosis in ApoE ⫺/⫺ mice when subjected to intraperitoneal
administration of exogenous IFN-␥ (562). Furthermore,
mice lacking either INF-␥ or the INF-␥ receptor (191, 358)
were less prone to atherosclerosis development than
were their wild-type controls.
IFN-␥ exerts its effects through a number of mechanisms that have been demonstrated in cultured cells. This
entails effects on 15-lipoxygenase (97), lipoprotein modification (91), lipoprotein-cell recognition (169), ECM synthesis (468), lipoprotein metabolism (242), and apoptosis
Physiol Rev • VOL
(171). Furthermore, IFN-␥ has been found to upregulate
CD38 expression, and it was suggested that CD38 may
play a specific role in the activation and adhesion processes to which monocytes are subjected (357).
7. IL-10
IL-10 is an anti-inflammatory cytokine produced by
activated monocytes and lymphocytes. IL-10 most likely
exerts its anti-inflammatory effects on the vascular system through inhibition of leukocyte-EC interaction and
inhibition of proinflammatory cytokine and chemokine
production by monocytes/macrophages or lymphocytes
(321, 322, 417). Studies have been presented showing
evidence that IL-10 can inhibit MM-LDL-induced monocyte-endothelium interaction as well as atherosclerotic
lesion formation in mice fed an atherosclerotic diet (411).
In this study, IL-10 null mice were associated with increased lesion formation compared with either control or
IL-10 transgenic mice. Similar results were obtained by
another group (321). IL-10 exerts its biological effects on
cells by interacting with a specific cell-surface receptor
(see review in Ref. 518).
8. Transforming growth factor-␤
Transforming growth factor-␤ (TGF-␤) is found in
highest concentrations in platelets (185). It has both
proatherogenic as well as antiatherogenic effects since it
stimulates macrophage secretion of various growth factors such as, e.g., PDGF, and secretion of extracellular
matrix proteins, e.g., collagen and proteoglycans (88,
459). Furthermore, macrophage chemotaxis and TIMP
secretion are primed by TGF-␤. On the other hand, TGF-␤
inhibits production of reactive oxygen and nitrogen metabolites in activated macrophages (for reviews, see Refs.
55, 126). TGF-␤1 downregulates cytokine-induced expression of E-selectin and VCAM-1 in endothelial cells (124,
395) as well as VCAM-1 in SMC (488). The effect of
TGF-␤1 on human umbilical vein EC (HUVEC) stimulated
with TNF-␣ or IL-1␤ entails downregulation of MCP-1
expression through downmodulation of TNF receptors
(219). IL-8 production by TNF-activated EC as well as
inhibition reversal of IL-8-dependent migration of neutrophils through the activated endothelial monolayer are
inhibited by TGF-␤1 (488).
Although the proinflammatory effects of the substantial number of cytokines are well documented, their exact
role in lesion formation in the early phase of atherogenesis is still unresolved. Furthermore, because most of the
anti-inflammatory cytokines, except IL-1ra, have at least
some proinflammatory properties as well, the importance
of the various cytokines in the early phase of atherogenesis is still open to debate.
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
IL-12 is a heterodimeric protein in which the 35-kDa
and 40-kDa subunits are linked by two disulfide bridges.
This cytokine is produced by phagocytic cells, dendritic
cells, skin Langerhans cells, and B cells. IL-12 induces
IFN-␥ in NK cells and T cells, thereby shifting T-cell
differentiation toward a TH1 response. It stimulates
growth of activated NK cells, CD8⫹ T cells, and CD4⫹ T
cells (for a review, see Ref. 25). Furthermore, IL-12 increases production of TNF-␣, which acts in synergy with
IFN-␥, and it suppresses IL-4-induced IgE production. It
has been suggested that IL-12 may play an active role in
regulating the immune response during the early phase of
atherosclerosis in apoE-deficient mice (284).
1085
1086
BJARNE ØSTERUD AND EIRIK BJØRKLID
D. CD14 Polymorphism on the Gene
of the CD14 Receptor
Physiol Rev • VOL
VII. CELLULAR SIGNALS INVOLVED
IN MONOCYTE ACTIVATION
A. Role of Phospholipases
Phospholipase A2 (PLA2) catalyzes the hydrolysis of
phospholipids, like phosphatidylcholine (PC), phosphatidylserine (PS), or phosphatidylethanolamine (PE) (489), at position sn-2, where arachidonate is most frequently located
(350). The released free arachidonic acid in turn serves as
substrate for two major pathways, the lipoxygenase (LO)
pathway and the cyclooxygenase (CO) pathway, leading to
the generation of leukotrienes and prostaglandins, respectively (Fig. 3). The other product derived from the PLA2dependent cleavage is lysophospholipid.
Two major PLA2 are found in monocytes/macrophages, a secretory type (sPLA2) and a cytosolic type
(cPLA2), respectively. sPLA2 (14 kDa) is stored in granules for release to the extracellular milieu upon leukocyte
activation (29, 526). This enzyme probably remains inactive within the granules, becoming functionally active
only when exocytosed (for a review, see Refs. 328, 355).
The substrates for sPLA2 are phospholipids exposed at
the outer surface of the plasma membrane (Fig. 2).
Recently, it was shown that when monocytes were
treated with SB 203347, a specific inhibitor directed
against the active site of sPLA2, leukotriene and PAF
formation were totally blocked, whereas the production
of prostanoids remained unaffected (328). On the other
hand, an inhibitor of cPLA2 blocked the generation of
prostanoids but not leukotriene C4 (LTC4) or PAF in
zymosan-stimulated monocytes (328). Thus the evidence
suggests that sPLA2 provides substrate for monocyte leukotriene and PAF formation, whereas cPLA2 plays a more
significant role in prostaglandin generation. This is in
agreement with an earlier report showing that depletion
of human monocyte 85-kDa PLA2 did not significantly
affect the leukotriene formation (329).
cPLA2 (85 kDa) is a monomeric enzyme located primarily in the cytosol of unstimulated cells, in segregation
from its substrate. In activated cells, cPLA2 is effectively
regulated by the elevated cytosolic calcium levels,
whereby binding of the enzyme via an amino-terminal C2
domain is facilitated (Fig. 2). The C2 domain is a conserved Ca2⫹-triggered membrane-docking module that
targets numerous signaling proteins to membrane surfaces where they regulate diverse processes critical for
cell signaling (365). Thus translocation of the enzyme to
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
The leucine-rich 55-kDa membrane glycoprotein
CD14, better known as the LPS receptor, is significantly
expressed by mature monocytes, macrophages, and activated neutrophil granulocytes (183). Anchored at the cell
surface (see Fig. 2), it facilitates cellular internalization of
LPS (463). Other agonists, notably the heat shock protein
HSP70, also activate monocytes by binding to CD14 (18).
Two European groups reported for the first time a relationship between promoter polymorphism in the CD14
gene and increased risk of atherosclerosis (225, 533). One
group found that T⬎C at position ⫺159 was associated
with increased risk of myocardial infarction, and the
other reported C⬎T at postion ⫺260 was more frequent in
myocradial infarction survivors than controls. Recently,
two Japanese groups confirmed the occurrence of the C
(⫺260)3 T nucleotide change and an associated predisposition to increased risk of coronary artery disease (235,
480). The polymorphism was apparently associated with
an enhanced risk for myocardial infarction (MI), particularly in patients who did not otherwise have any significant risk profile for atherosclerosis. Because the polymorphism is associated with an upregulation of CD14 receptors on monocytes, these observations corroborate the
growing evidence that chronic infections of, e.g., Chlamydia pneumonia, Helicobacter pylori, Epstein Barr virus, etc., may be important risk factors for the development of atherosclerosis and consequently of MI. Whether
CD14 polymorphism is the much sought for culprit underlying the prevalence of high responder monocytes in families with high incidence of MI (385) is an issue that would
need further investigation.
A deviating pattern of differentiated subpopulations
of monocytes has been documented in hypercholesterolemic compared with normocholesterolemic individuals
(446). Thus, in a group of hypercholesterolemic patients,
HDL-cholesterol levels correlated negatively with the
population size of CD64⫺CD16⫺ monocytes [monocytes
that lack FcRI (CD64) and FcRIII (CD16)], whereas on the
other hand, plasma LDL-cholesterol and lipoprotein (a)
levels correlated positively with expression of the variant
antigen CD45RA in peripheral blood monocytes. Cellular
activation has been shown to increase the expression of
CD45RA at the cell surface in vitro (71). On the other
hand, cells lacking CD64 show lower expression of CD14
antigen but higher expression of MHC II antigen, i.e., they
have a higher capacity for antigen presentation and a
deviant pattern of stimulus-induced cytokine release response compared with the predominant monocyte phenotype of peripheral blood (184). This appears to fall in line
with the failure to see enhanced monocyte reactivity in
the blood of hypercholesterolemic patients (382, 385).
Furthermore, a high number of healthy individuals in
families with a high risk of atherosclerosis despite normal
cholesterol levels appeared to have hyperactive monocytes (385). Accordingly, high reactivity of peripheral
monocytes was proposed to be a risk factor for coronary
artery disease.
MONOCYTES IN ATHEROGENESIS
1087
the nuclear envelope and the endoplasmic reticulum is
induced. A transient calcium flux may cause only reversible and transient translocation of cPLA2, insufficient for
arachidonic acid release, whereas a more substantial and
persistent flux may lead to prolonged perinuclear translocation and arachidonic acid liberation (215, 418). In
intact cells, MAPK-dependent serine phosphorylation of
cPLA2 may also be required for arachidonic acid release
(306).
As documented in vivo, cPLA2 activity may also be
indirectly regulated by inhibition at the level of of phosphatidylinositol 4,5-bisphosphate (PIP2) generation, effectively reducing cPLA2-mediated arachidonic acid metabolism (30). This may entail an alternative and calciumindependent mechanism of cPLA2 translocation to and
interaction with membranes.
The cartoon depicted in Figure 2 shows how cPLA2
and sPLA2 and their activities comprise part of the transduction mechanism systems for monocyte activation.
Physiol Rev • VOL
B. Role of Phospholipases in Atherosclerosis
1. sPLA2
sPLA2 has been detected in atherosclerotic lesions of
the aorta, where it colocalized with macrophages and
SMC and has also been found extracellularly in the lipid
core (229, 291, 341, 456). This sPLA2 was fully active and
capable of hydrolysis of LDL phospholipids, promoting
the release of proinflammatory lipid products at LDL deposition sites of the arterial wall. The activity was upregulated via binding to decorin, a small proteoglycan with
chondroitin/dermatan sulfate glucosaminoglucans comprising an integral part of the collagen network in human
arteries (237, 291, 454).
Direct evidence that sPLA2 may promote atherogenesis was obtained in transgenic mice expressing sPLA2
(237, 291). These mice had a dramatically higher incidence of atherosclerotic lesion development than had
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
FIG. 3. Biosynthesis of prostanoids, thromboxane, leukotrienes, lipoxins, and HETEs. Numerous stimuli may
activate phospholipase A2, which hydrolyzes membrane phospholipids releasing arachidonic acid (AA). AA may be
metabolized by cyclooxygenases (COX-1 and COX-2) into PGH2, which may be converted to thromboxane A2 (TxA2),
prostacyclin (PGI2) or other prostaglandin-type metabolites. AA is also the subtstrate for lipoxygenases (LO) whereby
leukotrienes (LT), HETEs, or lipoxins are produced. Cytochrome P-450 is converting AA into HETEs, which may be
further metabolized to dihydroxyeicosatrienoic acids (DHETs) and 1,20-eicosatetraenedioic acid (20 COOH-AA).
1088
BJARNE ØSTERUD AND EIRIK BJØRKLID
2. cPLA2
By inference from several studies cPLA2 is considered a principal mediator of LDL oxidation. In human
monocytes activated by opsonized zymosan, both cPLA2
protein and enzymatic activity were induced. The cPLA2
activity was inhibited in a dose-dependent manner by the
specific inhibitor AACOCF3, and there was a concomitant
reduction in LDL oxidation, whereas sPLA2 remained unaffected (299). When activated monocytes were exposed
to antisense oligonucleotides inhibiting cPLA2 expression, the cells had a markedly reduced capacity for O2
production and for mediating LDL lipid oxidation.
The crucial role of cPLA2 in the oxidation of LDL
notwithstanding, other PLA types probably also contribute to the atherogenic process by initiating the generation
of proinflammatory mediators. Thus sPLA2 was detected
immunohistochemically in macrophages of the intima of
early atherosclerotic lesions (456), and it also turned out
to be induced by mildly oxidized LDL in monocyte-derived macrophages in vitro (12). Enhanced expression of
cPLA2 was induced in vitro after 2–3 days in monocytes
Physiol Rev • VOL
undergoing differentiation to macrophages, thus constituting part of this differentiation process, whereas sPLA2
was only expressed in further stimulated mature macrophages. Interestingly, the transcription of sPLA2 in macrophages could be induced by adding minimally oxidized
or otherwise modified LDL, whereas native, extensively
oxidized, or acetylated LDL had no significant effect to
this end. Taken together, the results suggest that both
sPLA2 and cPLA2 have proinflammatory and proatherogenic potentials by way of their roles in monocyte/macrophage functioning.
The peritoneal macrophages of cPLA2 knock-out
mice produced markedly less LTB4, LTC4, PGE2, and PAF
than did those of wild-type mice, when activated with
calcium ionophore or LPS (60, 481, 534). This is strong
evidence that cPLA2 is mandatory for eicosanoid generation in the mouse strain used. No such requirement could
be demonstrated in mouse strains naturally deficient in
sPLA2, but still able to generate normal levels of LTC4,
PGD4, and mast cell PLA2 (51, 432). Furthermore, cells of
the mouse macrophage line P388D1 lacking detectable
transcripts for sPLA2, and osteoblasts derived from mice
deficient in sPLA2, maintained normal PGE2 production
(28, 354).
C. Pathways for Arachidonic Acid Conversion
1. Cyclooxygenases
The activation of monocytes/macrophages is rapidly
followed by the generation of prostanoids and leukotrienes. Prostanoids are cyclooxygenase-dependent products of arachidonic acid (n-6, 20:4, 5, 8, 11, 14) metabolism, comprising PGD2, PGE2, PGF2␣, and prostacyclin
(PGI2), and TxA2 (Fig. 3). Once released, they act locally
on neighboring cells, via G protein-coupled receptors containing seven transmembrane domains (130). So far eight
types and subtypes of prostanoid receptors have been
identified. The subtypes are encoded by different genes
and constitute a subfamily within the superfamily of the
rhodopsin-type receptors (368).
As shown in Figure 3, prostanoid and thromboxane
generation depends on two distinct enzymes with cyclooxygenase activity, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), respectively (for a review, see Refs.
368, 467). COX-1 is constitutively expressed in cells,
whereas COX-2 may be induced (187) and expressed in a
sustained manner during severe inflammatory reactions.
COX-2 is the principal enzyme providing a mechanism for
the generation of proinflammatory prostanoids (368).
Constitutively expressed COX-1 has been detected
widespread in all human tissues (377). The extent of
enzyme expression and accompanying prostaglandin production in these different tissues may vary considerably,
in correlation with the severity of the inflammatory con-
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
regular mice, when maintained on a high-fat, high-cholesterol diet or even when given a low-fat Chow diet. Immunohistochemical staining revealed the presence of sPLA2
in the atherosclerotic lesions, and the mice had lower
high-density lipoprotein (HDL) and higher LDL/very-lowdensity lipoprotein (VLDL) levels than did wild-type mice,
accompanied by significantly decreased paraoxonase activity in their plasma. Paraoxonase is a HDL-ester hydrolase with a proven capacity of hydrolyzing lipid peroxides
in vitro. Thus it may destroy biologically active phospholipid peroxides by acting as a phospholipase hydrolyzing
sn-2 ester bonds (553), and it is known to account in part
for the inhibition of LDL oxidation by HDL. A profound
inhibitory effect of paraoxonase on cell-mediated LDL
oxidation in vitro has been demonstrated (479, 553). Paraoxonase in HDL may protect against the induction of
inflammatory responses in cells of the artery wall, by
destroying biologically active lipids present in mildly oxidized LDL (553) (Fig. 1). Recently, it was shown that
polymorphisms in the paraoxonase gene are associated
with carotid arterial wall thickness in subjects with familial hypercholesterolemia (295). However, the role of human paraoxonase is still debated, as some populationbased studies have not found any association between
polymorphisms in the gene that encodes paraoxonase and
CHD (22).
Acute phase responses typical of chronic inflammatory conditions like, e.g., arthritis, frequently entail severalfold enhanced circulating sPLA2 as part of their profile.
This has been suggested as a vehicle underlying the observed prevalency of coronary artery disease in conjunction with many chronic inflammatory diseases (237).
MONOCYTES IN ATHEROGENESIS
2. Prostanoid and thromboxane products
Certain prostanoids, such as PGE2 and PGI2, typically
mediate anti-inflammatory signaling via cAMP increase
(59, 368), in effect leading to a downregulation of monocye/macrophage activation (59, 66). Furthermore, PGI2
also downregulates inflammation by way of its antiplatelet effect and by promoting vasodilation. On the other
hand, TxA2 is known to have proinflammatory and prothrombotic effects (for review, see Refs. 131, 477), being
a very potent agonist of platelet activation, and also serving as a vasoconstrictive PG product. Studies on TxA2
receptor deficiency mice revealed increased bleeding tendency and resistance to cardiovascular shock (523).
TxA2 has been identified as the dominant cyclooxygase-dependent metabolite of monocytes, with lesser
amounts of PGE2, PGF2␣, and PGI2 being formed in declining order (398, 399). However, the powerhouse for
Physiol Rev • VOL
TxA2 generation in blood is the platelets. When rabbits
were given the TxA2 antagonist UK-38485 in conjunction
with a high-cholesterol diet, lesion formation was reduced, in accordance with the proinflammatory potential
of TxA2 (486). In low responder rabbits, treatment with
UK-38485 significantly reduced the percentage of the thoracic aorta surface covered by lesions, an effect not seen
when high responders were used. The area covered did
not correlate with serum cholesterol levels.
3. Isoprostanes
Isoprostanes are prostaglandin isomers that are primarily generated by free radical oxidation from arachidonic acid (348, 376a). In addition to serving as useful
indices of oxidant stress in vivo, isoprostane effects exerted on cells in vitro have been demonstrated. Thus
9a,11a,15S-trihydroxy-(8b)-prosta-5Z,13E-dien-1-oic acid
(iPF2␣-III) activates the receptor for TxA2 (the TP) (20).
This latter compound and the analgous iPE2-III modulate
platelet function and adhesive interactions between platelets and endothelial cells (289, 580) and are also potent
vasoconstrictors in vitro and in vivo (213, 512). Immunohistochemical studies have shown that foam cells adjacent to the lipid necrotic core of plaques were markedly
positive for iPF2␣-III (415).
3. Cytochrome P-450-derived products
Several oxygenases have been implicated in the process of LDL oxidation in the arterial wall. Among these
the cytochrome P-450, which is expressed in monocytes/
macrophages (35), has been shown to induce LDL oxidation in vitro, where it also was demonstrated that hydrogen peroxide and superoxides were involved (24). The
fact that some of the P-450 enzymes are present in liver
and in arterial wall has prompted the suggestion that they
are pathophysiologically relevant in conjunction with LDL
oxidation and atherogenesis. Cytochrome P-450 enzymes
may metabolize arachidonic acid, leading to many biologically active compounds (see Fig. 3), some of which are
potent regulators of vascular tone (376).
4. Lipoxygenases and LO-dependent products
The lipoxygenases comprise a class of nonheme iron
dioxygenases recognizing the 1.4-pentadienyl structure of
polyunsaturated fatty acids, catalyzing single oxygen molecule incorporation at specific sites and the formation of
dienic fatty acid hydroperoxides (574, 575). The classic
substrate is arachidonic acid released from membranes
by PLA2 (Fig. 3). Different types of lipoxygenases are
specified by the numbering of the target carbon in their
substrate, i.e., 5-LO catalyzes oxidation at C-5 (61), and
12-LO and 15-LO at C-12 (197) and C-15 (198), respec-
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
dition. However, the role of COX-1 is overshadowed by
that of the apparently more important COX-2 enzyme
(541, 564). Inducible COX-2 has been found in fibroblasts
(135), mucosa cells (441), macrophages as well as atheroma-associated cell types like SMCs and endothelial
cells (16, 380, 438) in a variety of tissues (377).
The constitutive expression of COX-1 in nonatherosclerotic arteries as well as in atherosclerotic lesions
(458) suggests that the enzyme has a role under physiological conditions in maintaining homeostasis, rather than
having a role during inflammation (308). Selective studies
on human carotid artheroma and healthy aorta revealed
that atherosclerotic lesions contained both COX-1 and
COX-2. The enzymes colocalized mainly with macrophages in the shoulder region of the atheroma and with
the peripheral region of the lipid core, whereas in healthy
SMC the levels of these enzymes were comparatively less
pronounced. The enhanced COX-2 expression detected
within such a focal site of chronic inflammation is in
accordance with earlier studies reporting COX-2 expression in cells that typically reside in atheroma, including
macrophages, SMC, and EC, in a manner dependent on
stimulation with cytokines such as TNF-␣ and IL-1␤ (16,
380, 438).
The mechanisms whereby the various products from
the cyclooxygenase pathway affect the atherogenic process remain only partly charted. Two classes of receptors
may transduce signals in response to prostaglandin ligand
binding: G-coupled membrane receptors (69) and the nuclear PPAR class (157). The two COX isoforms may in
part exert different functions by way of their location in
partially separated cellular compartments (347). Thus
COX-2 is located in the perinuclear region, which is relatively low in COX-1 (Fig. 2). In a recent study it was found
that COX-2 promotes early atherosclerotic lesion formation in LDLR-deficient mice (76).
1089
1090
BJARNE ØSTERUD AND EIRIK BJØRKLID
Physiol Rev • VOL
cilitated by a membrane protein termed 5-lipoxygenaseactivating protein (FLAP) (434). FLAP was previously
seen as a docking protein for 5-LO, but its role has now
been shown to be that of binding and presenting free
arachidonic acid to 5-LO, thereby promoting the oxygenation reaction (2).
The metabolic product of the 5-LO-dependent reaction is LTA4, which may in turn be converted to LTB4 via
LTA4 hydrolase activity, in a reaction eventually leading
to suicide inactivation of the hydrolase (154). Alternatively, LTA4 may be converted to LTC4 by the enzyme
LTC4 synthase.
There is some cross-talk of significance between the
12/15-LO pathways and the 5-LO pathway. Both 15HPETE and 12-HETE suppress 5-HETE and LTB4 production, and conversely, it has been shown that 5-HETE
inhibits 15-HETE production in rabbit PMN (536, 537).
Furthermore, 15-HPETE, but not 15 HETE, downregulates Fc ␥-receptors on human T cells and monocytes
(180). Also, 15-HPETE downregulates important proinflammatory processes, such as LPS-induced TNF-␣ production in monocytes and TNF-␣-induced expression of
ICAM-1, E-selectin, and VCAM-1 via protein kinase C
(PKC)-dependent pathways (151, 224).
Although 12/15-LO activity leads to the generation of
several products anticipated to have important anti-inflammatory properties, a number of dioxygenation products have a documented proinflammatory potential (259,
473). Thus, for example, 8,15S-diHETE is a neutrophilic
chemotactic factor. 12/15-LO is also essential for the generation of another important group of eicosanoids called
lipoxins (see Fig. 3). These are trihydroxy metabolites of
arachidonic acid, and the enzymes involved are either 12or 15-LO in conjunction with 5-LO. The cellular effects of
the lipoxins are mediated in part by G protein-coupled
receptors (153, 513). Because monocytes/macrophages
do express both 5- and 15-lipoxygenases, they are capable
of generating lipoxin products, e.g., lipoxin A4 and lipoxin
B4, which have potent anti-inflammatory properties usually counteracting any opposite effects of 5-lipoxygense
metabolites (203, 471).
D. Role of Lipoxygenases in Atherogenesis
Evidence that lipoxygenases are critically involved in
atherogenesis has recently emerged from various transgenic mice studies. Thus mice with ApoE deficiency
(ApoE ⫺/⫺) in combination with a 12-LO ⫺/⫺ trait had
significantly reduced tendency to lesion formation compared with mice with the ApoE ⫺/⫺ trait only (107). This
observation falls in line with the known prerequisite of
12-LO for monocyte chemotactic activity (371), and the
recent report that 12-LO products, notably 12-HETE, play
an important role modulating MM-LDL induction of
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
tively. Along with 8-LO (163, 276, 498), they are the only
lipoxygenases identified in mammalian cells thus far.
There are two subtypes of 12-LO, one of which has
been isolated from platelets. The other subtype, commonly referred to as leukocyte-type 12-LO, has been
found in murine, porcine, bovine, and canine species.
Leukocyte 12-LO is very different from platelet 12-LO and
more closely related to mammalian 15-LO (577). The biochemical activity of 15-LO is quite distinct and differs
from that of the other lipoxygenases in several ways.
Whereas 5-LO and platelet 12-LO are rather substrate
selective in preferring free arachidonic acid, leading to
the products hydroperoxieicosatetraenoic acid (HPETE)
and hydroxyeicosatetraenoic acid (HETE), 15-LO and the
leukocyte type 12-LO may act on a variety of free or
esterified polyenoic fatty acids (575, 574). With arachidonate as substrate, either of the latter two enzymes catalyze 15-HPETE and 15-HETE as well as 12-HPETE and
12-HETE generation. With linoleate as substrate, either
enzyme catalyzes 13-hydroperoxyoctadecadienoate (13HODE) formation. Furthermore, 15-LO and leukocyte
12-LO generate higher order oxygenation products including 5S,15S-diHETE, (5,15S-diHETE, 5-oxo-15-hydroxyHETE) and lipoxins (Fig. 3). In general, mono-HETEs,
mono-HPETEs, and lipoxins have inhibitory effects on
inflammation, whereas several of the di-HETEs have potent proinflammatory effects. Lipoxins, an acronym for
lipoxygenase interactive products, are trihydroxytetraenes typically formed by transcellular metabolism initiated by the sequential actions of 15- and 5-lipoxygenases
or 5- and 12-lipoxygenases depending on the cellular context. Lipoxins have been shown to inhibit P-selectin mobilization and attenuate CD11/CD18 expression on endothelial cells. Furthermore, in polymorphonuclear neutrophils (PMN), they inhibit chemotaxis, adhesion, and
transmigration; stimulate IL-4 production; and inhibit cytokine-stimulated IL-1␤ and superoxide production (for
review, see Ref. 121). In monocytes, lipoxins stimulate
chemotaxis and adhesion (318).
Whereas circulating monocytes are devoid of 15-LO,
tissue macrophages do express the enzyme (101, 296).
Thus exposure to exogenous stimuli is apparently mandatory in order for 12-LO and 15-LO to be significantly
expressed in monocytes/macrophages, a situation that is
likely to arise when these cells are recruited into inflammatory tissue. The enzyme has been localized at sites of
macrophage accumulation in the artery wall of cholesterol-fed animals (214, 584). 15-LO has been shown to
colocalize with epitopes of oxidized LDL (584).
5-LO is localized in the cytosol of resting monocytes
(570) and neutrophils (405) of peripheral blood. It is
translocated to the nuclear envelope in response to cellular activation and the ensuing rise in intracellular calcium (177, 405, 457), where it has a role in the hydrolysis
of phospholipids (406). The lipoxygenase reaction is fa-
MONOCYTES IN ATHEROGENESIS
Physiol Rev • VOL
5-LO is the rate-limiting enzyme in leukotriene synthesis. When a 5-LO knock-out allele was bred into LDL
receptor-null (LDLR ⫺/⫺) mice, these mice showed a
dramatic decrease in aortic lesion development (340). In
line with this report is a very recent study which shows an
important role for LTB4 (5), a major product in the 5-LO
pathway (see below).
1. The lipoxygenase products LTB4, LTC4, and LTD4
The activation of monocytes and macrophages is
associated with a significantly enhanced production of
LTB4. Residential alveolar macrophages generate severalfold more LTB4 than do circulating monocytes (31, 48).
Although LTB4 is of prime importance, it is but one of
several lipoxygenase products generated upon cellular
activation.
An array of functional properties is exhibited by
LTB4, in conjunction with phenomena such as chemotaxis, modulation of cytokine production, IL-2 receptor
and c-fos and c-jun expression, tumor cytotoxicity in
monocytes and macrophages, as well as the production of
IFN-␥, IL-2, IL-4, IL-5, and IL-10 in lymphocytes, probably
rendering this the principal proinflammatory LO product
in atherogenesis. Interacting with endothelial cells, it promotes leukocyte adherence to the endothelium (221),
thus facilitating monocyte recruitment and LDL oxidation
at the endothelial surface. Furthermore, interaction of
LTB4 with receptors on monocytes and PMN (178, 275,
433) leads to an amplified activation of these cells, entailing induction of oxygen radical formation and augmented
release of reactive oxygen metablites, PAF (501), cytokines (440), and proteases (103).
By way of its role as a powerful mediator of inflammatory reactions, LTB4 promotes events that are likely to
be of vital importance in atherogenesis. Such a role for
LTB4 would be in accordance with the notion that chronic
infectious diseases provide thriving conditions for the
emergence of CHD, a subject discussed in more detail
later in this review. LTB4 has been shown to depend for
its functional activity on a LTB4 receptor, the recently
cloned gene of which codes for a protein predicted to
have seven membrane-spanning domains (585). Like
other transmembrane proteins of this type, it is coupled to
a heterotrimeric G protein, which varies between cells
expressing the receptor, thereby allowing for a diversity
in responses. Considering the above properties of LTB4
and its receptor, it appears sensible that a LTB4 receptor
antagonist reduced lesion formation in LDLR ⫺/⫺ mice
(5). Interestingly, it was also found that LTB4 antagonism
had no significant effect on lesion size in mice possessing
the null alleles for MCP-1 (MCP-1 ⫺/⫺ ⫻ LDLR ⫺/⫺),
suggesting that MCP-1 and LTB4 may either interact or
exert their effects by a common mechanism.
Although both LTC4 and LTD4 were reported to stim-
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
monocyte binding to endothelial cells (219). In the latter
study, either of the LO inhibitors 5,8,11,14-eicosatetraynoic acid (ETYA) and cinnamyl-3,4-dihydroxy-␣-cyanocinnamate (CDC), when used at concentrations
claimed to specifically abolish 12-LO activity, also
blocked monocyte binding to MM-LDL-treated endothelial
cells.
15-LO was initially hypothesized to have a role in LDL
oxidation, since it catalyzes the generation of available
peroxyl radicals (535). This hypothesis was supported by
studies showing that 15-LO inhibitors reduce EC- and
macrophage-mediated oxidation of LDL (338, 396, 426).
Isolated 15-LO actively exerts oxidative modifications of
LDL (41). Cells transfected with 15-LO gene had a higher
capacity for LDL oxidation than had cells transfected with
a control gene (44). Despite such observations, the suggested role of this enzyme in initiating LDL oxidation
remains controversial, the main issue being whether
15-LO could be the sole agent needed (41). However,
atherosclerosis induced in rabbits by a dietary regime was
attenuated by the administration of a highly specific 15-LO
inhibitor lacking significant antioxidant properties (53,
469). The finding in two animal models that benzothiopyranidole, another 15-LO inhibitor lacking significant antioxidant activity, could nonetheless eliminate lesion formation without significantly affecting plasma lipids (100),
is evidence to the same effect. Furthermore, in a recent
study using 12/15-LO-deficient (12/15-LO ⫺/⫺) mice that
had been crossed with ApoE-deficient (ApoE ⫺/⫺) mice,
it was found that urinary and plasma levels of the specific
isoprostane 8,12-iso-iPF2␣-VI, as well as IgG autoantibodies against MDA-LDL, were significantly reduced in the
double deficiency mice in parallel with decreased atherosclerosis, relative to ApoE ⫺/⫺ controls (106). It was
concluded that 12/15-LO contributes significantly to the
initiation and propagation of atherosclerotic lesion formation in mice. Furthermore, the strong correlations found
between lesion size, isoprostane levels, and MDA-LDL
autoantibodies is in vivo evidence for an enzymatic (12/
15-LO) component to lipid peroxidation in atherogenesis.
In apparent contradiction to the above results, transgenic rabbits expressing 15-LO in a macrophage-specific
manner and given a high-fat, high-cholesterol diet for 13.5
wk, developed less lesions than did nontransgenic rabbits
(476). It was suggested that the antiatherogenic effect of
15-LO might be mediated via the conversion of linoleic
acid into the platelet chemorepellent 13-HODE, inhibiting
platelet adhesion to the endothelium and stimulating PGI2
production in endothelial cells (472) and decreasing platelet TxA2 production (73, 74, 193). Current knowledge falls
short in resolving the contradictions inherent in the results issuing from the overexpression of 15-LO in rabbits
versus those obtained in the other knock-out studies. The
possibility of species-specific effects or secondary effects
derived from the gene manipulation cannot be ruled out.
1091
1092
BJARNE ØSTERUD AND EIRIK BJØRKLID
ulate cultured endothelial cells so as to synthesize PAF
and bind neutrophils (337), whether they are involved in
atherogenesis remains an open question. However, LTD4
has been shown to increase vascular smooth muscle cell
(VSMC) proliferation and induce IL-1␤ in these cells
(413). This may indeed be part of the inflammatory mechanism during atherogenesis.
E. Availability of Arachidonic Acid
F. PAF
1. Production and mechanism of action
PAF and eicosanoids are synthesized from a common
arachidonic acid precursor source (274, 589). PAF is synPhysiol Rev • VOL
2. Biological and pathophysiological effects
PAF has a variety of biological functions (Table 5),
and is implicated in many pathophysiological states.
TABLE
5. Biological effects of PAF
Primes or activates platelets, neutrophils (200), monocytes
(58, 382), macrophages (176), and SMC
Upregulates adhesion molecules in leukocytes and endothelial
cells, promotes migration of monocytes across the endothelium
(505)
Enhances the formation and action of oxidized LDL (554)
Enhances superoxide (O⫺
2 ) generation (252), CD11/CD18
(152) expression, and elastase/cathepsin G in neutrophils (67)
Induces production of VEGF (369), NO, and collagenase
(39)
In concert with oxidized LDL it induces TNF-␣ production
(160)
PAF activation of LPS-primed macrophages triggers fast
activation of cPLA2 intracellularly (158)
SMC, smooth muscle cell; VEGF, vascular endothelial growth factor; NO, nitric oxide; PAF, platelet activating factor; TNF-␣, tumor
necrosis factor-␣; LPS, lipopolysaccharide; PLA2, phospholipase A2.
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
Monocytes of whole blood appear to be activated
through PLA2-dependent pathways, generating products
like interleukins, TNF, and other cytokines, as well as
tissue factor (the trigger of blood coagulation) and growth
factors (383). This explains the extraordinary efficacy of
corticosteroids in bringing about inhibition of LPS-induced production of cytokines (544). Although it appears
that under certain conditions cytokine and tissue factor
synthesis may be induced through protein kinase C-dependent pathways, as seen from the several studies on
monocytes in cell cultures, it should be emphasized that
such studies are carried out under conditions that are
unlikely to allow for true mimickry of the chain of events
occurring in vivo (383). This was recently brought home
by the finding that acetyl salicylic acid (ASA) enhanced
LPS-induced tissue factor expression in human monocytes in vivo (403), as also found ex vivo in whole blood
(379, 387). In contrast, in cultured monocytes, ASA had an
inhibitory effect on LPS-induced tissue factor and cytokine generation (378). This discrepancy is most probably
caused by the activation of monocytes and subsequent
activation of protein kinase C system during the isolation
of cells (383).
The central role of PLA2 in atherogenesis is consistent with the above-mentioned ex vivo observations. Thus
the generation of available arachidonic acid appears to be
a limiting step regulating inflammatory reactions. More
specifically, one may hypothesize that this is of importance for the activation of monocytes/macrophages when
interacting with modified LDL in the intima, as well as for
activation processes mediated by autocrine and paracrine
mechanisms. The degree of phospholipase activation and
subsequent arachidonic acid formation is strongly influenced by the lipid composition of the cell membrane.
Dietary omega-3 fatty acid supplementation was reported
to induce changes in the fluidity of human leukocyte
membranes, associated with a 39% reduction in the release of arachidonic acid when the cells were exposed to
calcium ionophore in vitro (283).
thesized by either of two pathways (not shown): the
remodeling pathway or the de novo pathway, the former
being the principal pathway in leukocytes and endothelial
cells. PAF is secreted with the fluid phase from human
monocytes and eosinophils, whereas when synthesized by
the same pathway in endothelial cells it is translocated to
the plasma membrane and retained on the cell surface
(589). The remodeling pathway incorporates a PLA2-catalyzed step, whereby 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine is converted into 1-O-alkyl-2-lyso-sn-glycero3-phosphocholine (lyso-PAF), and this lyso intermediate
is then acetylated in an acetyl CoA:lyso-PAF acetyl transferase (lyso-PAF AcT)-dependent reaction to form PAF.
Cells do not produce PAF constitutively, but only when
exposed to an appropriate agonist stimulus.
The receptor protein (PAFR) for which PAF serves as
the cognate ligand belongs to the serpentine family of
receptors, characteristically spanning the plasma membrane seven times. The intracellular signaling evoked by
ligand binding is mediated by G proteins linking PAFR to
downstream signaling events, such as turnover of phosphatidylinositol, intracellular calcium fluctuation, and activation of protein kinase C and other kinsases (for a
review, see Ref. 402).
PAFR gene expression is regulated by various cytokines and eicosanoids (440), apparently in much the same
way in human monocytes, neutrophils, platelets, and Blymphatic cell lines (351), entailing up- as well as downregulation. Thus IFN-␥ caused PAFR upregulation in human monocytes, associated with enhanced response to
PAF (388), whereas PGE2-induced cAMP downregulated
the expression of PAFR in human monocytes, associated
with reduced responsiveness to PAF (522).
MONOCYTES IN ATHEROGENESIS
G. Eicosanoid Products Involved in the Activation
of Monocytes?
The failure of ASA in preventing the development of
lesions in animals subject to a high-cholesterol diet has
been taken as evidence for the notion that platelets do not
have any important role in atherogenesis (444). This view
has to be qualified in the light of more recent studies
where ApoE-deficient mice were treated for 11 wk with
either aspirin or the thromboxane antagonist S18886 (79).
The administration of aspirin gave a pronounced decrease
Physiol Rev • VOL
in TxB2 levels, significantly more so than did S18886,
indicating the greater efficacy of aspirin in preventing
platelet synthesis of TxA2. On the other hand, S18886
decreased the incidence of aortic root lesions and levels
of ICAM-1 in serum, effects that failed to manifest when
aspirin was administered. It was therefore suggested that
such blocking of thromboxane receptors inhibited atherosclerosis by a mechanism that did not interfere with the
binding of TxA2 to the platelets, but rather with the binding of some other agonist. Certain nonenzymatic activation products of arachidonic acid capable of stimulating
thromboxane receptors, such as F2-isoprostanes, were
the suggested prime candidates for such atherogenic
products. Alternative culprits suggested were HETEs,
products that depend on leukocyte or endothelial lipoxygenases or nonenzymatic lipid peroxidation processes for
their formation, and also have the capacity for promoting
signal transmission via thromboxane receptors (520, 539).
HETEs are increased in atherosclerosis (409, 539) and
have been localized to atherosclerotic plaques (323).
Using an ex vivo model of whole blood, we recently
found that the thromboxane receptor antagonist SQ 29548
significantly reduced LPS-induced TNF-␣ and TF, suggesting that very important mechanisms for the upregulation
of activation products in monocytes are mediated via this
receptor (135). This may in part be the explanation why
ApoE deficiency mice appeared protected against lesion
formation when the TxA2 receptor was blocked by an
antagonist (79). On the other hand, in the same model the
TxA2 synthesis inhibitor aspirin (ASA) enhanced LPSinduced TF and TNF-␣ (387), and in an in vivo human
model of endotoxin effects TF was correspondingly enhanced (403). This is consistent with the failure of ASA to
reduce or prevent the formation of lesions in animal
models (54, 508).
H. PPAR-␥ as Regulator of Monocyte/Macrophage
Function
Based on a whole body of research over the last
couple of years, there is an emerging understanding that
the PPAR-␥ has a role in relation to monocyte/macrophage functioning (263, 436). PPARs are ligand-dependent
transcription factors belonging to the nuclear hormone
receptor superfamily. Their function is to regulate genes
involved in controlling growth, morphogenesis, cellular
differentiation, and homeostasis (85, 262, 324). PPAR-␥
only becomes functional once it is heterodimerized with
the retinoid X receptor (RXR), the dimer functioning as a
transcription factor regulating genes linked to lipid metabolism (33, 168, 234, 262).
Three subtypes of PPAR, indexed ␣, ␤, and ␥, are
known, all having distinct tissue distribution patterns and
being associated with selective ligands (64, 261, 292, 460,
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
Thus, along with certain cytokines (TNF-␣, IL-1␤, IL-6), it
is probably one of the most important mediators of inflammatory responses, and it is also playing an essential
role in endotoxin shock (43) and ischemia reperfusion
injury (277).
A role of PAF in leukocyte adhesion in vivo has been
suggested (337) and was recently explored using P-selectin deficiency mice. These mice were entirely protected
from the usually deleterious effects of PAF injection.
Thus the characteristic state of shock and intestinal necrosis never appeared, and there was no mortality associated with the injection. It was concluded that P-selectin
plays an important role promoting PAF-induced injury in
mice and that selectins and the integrin-ICAM-1 system
work in concert in mediating the inflammatory response
to PAF in vivo (507). It has been shown that P-selectin has
a priming effect on monocytes, leading to enhanced PAF
synthesis (140, 560). These studies have prompted the
suggestion that P-selectin expressed on endothelial cells
or platelets may serve a dual role in anchoring monocytes
locally at sites of vascular inflammation or thrombosis
and in priming these cells for responses augmenting inflammation.
The migration of monocytes across unactivated endothelium in response to macrophage inflammatory protein-1␣ (MIP-1␣), RANTES, PAF, or MCP-1 was completely inhibited by monoclonal antibodies to the CD18
component of the CD11b/CD18 (Mac-1) complex on
monocytes, and the migration in response to C5a was
partially (75%) inhibited (92).
PAF enhances superoxide (O⫺
2 ) production, CD11b
expression, and elsastase/cathepsin G release by PMN, all
essential components in the pathophysiology of severe
inflammatory reactions. The oxygen radicals thus formed
may in turn act synergistically with PAF to potentiate
tissue injury (10).
In addition to upregulating cytokine/TF production,
PAF may have further proatherogenic roles in enhancing
the formation and action of minimally oxidized LDL (MMox-LDL) and promoting the induction of TNF-␣ production in concert with oxidized LDL, an important step in
lesion formation (Fig. 1) (160).
1093
1094
BJARNE ØSTERUD AND EIRIK BJØRKLID
Physiol Rev • VOL
evidence that increased expression of CD36 can further
accelerate this process; rather, it was proposed that the
levels of LDL cholesterol or the conversion of LDL to
ox-LDL may be the rate-limiting factors.
PPAR-␥ has been implicated in the regulation of the
vascular inflammatory gene responses (112). Fibrates are
synthetic ligands recognizing PPAR-␥ (156), thereby mediating the lipid-lowering activity of these drugs (494).
Significant evidence has emerged that the fibrates may
also exert a more direct antiatherogenic activity independently of their lipid-lowering activity, as shown in rabbits
fed a cholesterol-rich diet and treated with the PPAR-␥
ligand fenofibrate. By this regime a decreased tendency of
atherosclerotic plaque formation in the thoracic aorta of
the rabbits was seen, even in the absence of discernably
decreased plasma lipid levels (447). Furthermore, activation of PPAR-␥ expression in mice was associated with a
prolongation of the inflammatory response (116). Fibrates
have a downregulating effect on the production of IL-6
and TNF-␣ also in humans (319, 494). The PPAR-␥-dependent mechanism by which fibrates inhibit the vascular
inflammatory response appears to be via the interference
of PPAR-␥ with the NF␬B and AP-1 transactivation capacity, involving direct protein-protein interaction with p65
and c-Jun (112).
VIII. INFECTION, MONOCYTES,
AND ATHEROSCLEROSIS
Concurrent with the growing evidence that prevalence of CHD can only in part be explained by the classical risk factors, such as smoking, hypertension, and high
cholesterol levels, there has been an emerging shift in
focus that addresses the associations between atherosclerosis and certain persistent bacterial and viral infections.
The best evidence for a link between infection and
CHD derives from seroepidemiological studies focusing
mainly on three pathogens: Chlamydia pneumonia, Helicobacter pylori, and cytomegalovirus (CMV) (109). In a
recent population-based study, strong evidence was
found for a partial atherogenic role of persistent Chlamydia pneumonia infection, as judged by serological and
clinical data (334). The seroepidemiological and histopathological findings are corroborated by the results of
animal experiments and preliminary intervention studies.
Recently it was shown that Chlamydia pneumonia infection may directly induce differentiation of monocytes to
macrophages, and this may provoke the development of
atherosclerosis (572).
Helicobacter pylori has been associated with CHD in
several studies (cited in Ref. 109). How this should be
interpreted remains controversial, since these reports are
seemingly contradicted by data not supporting the notion
of Helicobacter pylori being a major independent risk
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
548). PPAR-␥ is a nuclear receptor, reported to regulate
glucose and lipid levels, and according to more recent
studies it is involved in regulating the cell cycle and in the
differentiation of monocytes and regulation of their function. The natural ligands for PPAR-␥ are 15-deoxy-prostaglandin J2 (15d-PGJ2), polyunsaturated fatty acids such as
linoleic acid and linolenic acid, oxidized LDL (527), and
two oxygenated linoleic acid derivatives, 9- and 13-hydroxy-octadecadienoic acid (9-and 13-HODE) (360). Furthermore, PPAR-␥ is activated by nonsteroidal drugs, as
shown using indomethacin (287).
Although the occurrence of PPAR-␥ was initially reported for whole tissue specimens, notably adrenal gland,
spleen, adipose, and colon tissues, more recently expression of PPAR-␥ in monocytes/macrophages has been confirmed (89, 239, 435). Like 12/15-LO, PPAR-␥ is induced by
IL-4 (104). IL-4-dependent expression of CD36 was impaired in 12/15-LO-deficient mice, and 12/15-LO has been
shown to potentiate PPAR-␥ activation by arachidonic
acid. Evidence suggests that PPAR-␥ may play some important dual role in atherogenesis, either promoting the
process or protecting against it depending on the conditions. The promoting potential possibly stems from an
upregulation of the scavenger receptor CD36 by PPAR-␥
in combination with RXR ligands, leading to increased
uptake of oxidized LDL and thereby enhanced foam cell
formation (360, 527). On the other hand, PPAR-␥ exerts
negative transcriptional control of the genes for TNF-␣,
IL-6, IL-1␤ (239) MMP-9 (gelatinase B) (332, 436), and
inducible nitric oxide synthase (95, 436) and inhibits gene
expression and migration in human vascular SMC (331)
(see Fig. 1).
Evidence for a direct role of PPAR-␥ in atherosclerosis has been provided by the detection of PPAR-␥ in
atherosclerotic plaques of transgenic mice carrying the
human Apo B100 and apolipoprotein (a) genes but lacking
the LDL receptor (527). Furthermore, PPAR-␥ has been
detected in foam cells of human atherosclerotic lesions
(332, 435), in a manner correlating with the presence of
oxidation-specific epitopes (435).
Although PPAR-␥ appears to serve both proatherosclerotic and anti-inflammatory and hence possibly antiatherosclerotic progressions, recent animal studies indicate that the overall effect of PPAR-␥ activation tends to
be predominantly antiatherosclerotic. This was documented using LDLR-deficent mice fed a Western-style diet
in combination with either of two different synthetic
PPAR-␥ ligands, thiazolidinedione (TZD) and GW7845,
both of which are capable of activating PPAR-␥ (298).
Either drug reduced the number as well as the size of
lesions in male mice, an effect that for unknown reasons
did not appear in females. An editorial commentary (442)
suggested that CD36 expression, although it is required
for foam cell formation, may not be rate limiting for the
process under ordinary circumstances. Thus there is no
MONOCYTES IN ATHEROGENESIS
A. C-reactive Protein and Its Relation
to Atherosclerosis
An abundance of evidence based on acute phase
protein markers in blood like CRP, fibrinogen, IL-6, albumin, and others suggests that inflammation is somehow
linked to atherothrombotic disease in middle-aged popuPhysiol Rev • VOL
lations (528). The fact that these markers may be of
prognostic significance for events occurring even after
considerable periods of time is in accordance with the
notion that inflammation may be associated with all
phases of atherothrombotic disease.
C-reactive protein (CRP) is an acute phase protein
associated with inflammatory reactions and infections.
Several recent studies have focused on its relation to
cardiovascular diseases. Thus CRP has been found to
have predictive power for future myocardial infarction
and stroke in middle-aged men and women without clinical cardiovascular disease, independently of the incidence of other established risk factors (437).
The question has been raised, earlier for fibrinogen
and more recently for CRP, whether these acute phase
proteins are just markers of inflammation or somehow
directly linked to the atherogenic process. Several mechanisms can be envisioned whereby CRP might contribute
to the process, including induction of monocyte TF (83),
complement activation (569), and cell-cell interaction
(590).
In contrast to the tenet of the classical hypothesis
regarding foam cell formation in atherogenesis, recently a
mechanism for LDL uptake was suggested that did not
hinge on any biochemical modification of LDL (591). In
this study, LDL uptake turned out to be mediated by the
plasma factor CRP. Thus uptake of CRP in complex with
LDL was mediated by CD32 in a serum-dependent reaction, in line with former reports on CRP-mediated opzonization of biological particles (349).
IX. THE PROINFLAMMATORY PLATELET
AND ITS ROLE IN THE EARLY PHASE
OF ATHEROGENESIS
Although platelets have been implicated in the pathogenesis of atherosclerotic lesions for a very long time
(134), the issue whether they play an important role in the
early phase of lesion formation has not been resolved. In
our opinion, platelets are most likely part of the early
mechanism of atherogenesis. This hypothesis is based on
the proinflammatory properties of platelets.
Activated platelets secrete a number of chemokines
of both the CC and CXC subgroups (414), most of which
are known to be stored in the ␣-granules (247, 264, 452).
The chemokine RANTES is characteristically targeting
lymphocytes, monocytes, and eosinophils (247, 455), thus
mediating release of histamine from basophils (279) and
exocytosis of eosinophil cationic protein, and it also
serves as a stimulant for leukotriene formation (445) and
IL-8 production (559). Recently, it was shown that the
deposition of RANTES by platelets triggers shear-resistant monocyte arrest on inflamed or atherosclerotic endothelium (543). Thus exposure of platelet-derived RANTES
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
factor for CHD (267). However, Helicobacter infections
are associated with a prevalence of antibodies to the heat
shock protein HSP60. Antibodies to bacterial heat shock
proteins, notably HSP60, cross-react with the human antigen counterpart, and this has been suggested to evoke
an autoimmunity response implicated in atherosclerosis
(173, 571). In line with this scenario, bacterial HSP60 has
been found colocalized with human HSP60 in atherosclerotic plaques (271).
HSPs are intracellular proteins generally perceived
as serving protective functions under conditions of infection and cellular stress. There is a risk of autoimmunity
associated with HSPs, due to their high interspecies sequence homology, throughout the range from prokaryotes
to humans (586). Recently it was found that human as
well as chlamydial HSP60, both detected in human atheroma, can activate vascular cells and macrophages (269)
(Fig. 1). Furthermore, added Chlamydia HSP60 mediated
activation of cultured peripheral blood monocytes and
monocyte-derived macrophages in a CD14-dependent
fashion, i.e., via the same receptor for which bacterial LPS
is also a ligand (270).
Thus autoimmune stimulation via HSPs may be part
of the mechanisms by which chronic infections may promote atherogenesis. Infectious organisms may also affect
the atherosclerotic process by way of direct local interactions with the coronary endothelium, vascular SMC,
and macrophages within the atherosclerotic lesion. Even
more important and linked to the wide ranges of monocyte and platelet reactivities, under given conditions of
hyperreactivity the infection may exert systemic effects
via monocyte activation and ensuing cytokine production.
Thus low-grade hypercoagulability states and inflammation may be promoted, eventually leading to lesion formation.
Whether a single microbial agent may be responsible
for atherosclerosis has been questioned. It has been
shown that nonspecific (endotoxin) stimulation of the
immune system accelerates atherosclerosis in rabbits on
a hypercholesterolemic diet (288). In line with this concept, it has been shown that seropositivity for one single
pathogen did not have predictive power regarding risk for
coronary artery disease (CAD), whereas on the other
hand, the number of infection pathogens to which an
individual has been exposed (infectious burden) did correlate with CAD (21).
1095
1096
BJARNE ØSTERUD AND EIRIK BJØRKLID
Physiol Rev • VOL
A recent study suggested a more direct link between
platelets and development of atherosclerosis based on the
evidence for a role of vWF in atherogenesis (343). It has
been established that vWF, present in plasma, platelet
␣-granules, Weibel-Palade bodies of endothelial cells, and
the subendothelium (546) is involved in thrombus formation at the site of atherosclerotic plaque rupture (26). On
the other hand, the notion that vWF should have any role
in atherosclerotic lesion formation has been less clearly
underpinned. In a study using vWF-deficient mice interbred with an atherosclerosis-susceptible LDLR ⫺/⫺
strain, and fed a diet rich in saturated fat and cholesterol,
it was found that in the absence of vWF lesion formation
was reduced relative to the LDLR ⫺/⫺ control, primarily
at flow-perturbed regions of the aorta typically prone to
atherosclerosis. vWF expression is particularly prominent
near branch points and bifurcations (470). Further evidence that platelets may play a role in the early phase of
atherogenesis has emerged from a study where hypercholesterolemia primed platelets for recruitment via vWF,
glycoprotein IB (GPIB) alpha, and P-selectin to lesionprone sites, before lesions are detectable (521). It can be
concluded that vWF may recruit platelets and with them
leukocytes to the lesion in a flow-dependent manner.
Platelets thus interacting with an activated endothelium
in a vWF-dependent manner may contribute to the atherosclerotic process by releasing growth factor and other
proinflammatory products. In addition, many years ago it
was shown that platelets adhere and aggregate to the
endothelium of aortas of mice not exposed to any experimental injury (244). It was suggested that the adherence
of platelets to the vessel wall induced injury of the intimal
tissue through the release of vasoconstrictive agents from
the platelets.
Yet another indirect clue for a role of platelets in
early atherogenesis has been provided by the demonstration that activated platelets induce significantly enhanced
secretion of MCP-1 (also shown before in Ref. 559) and
surface expression of ICAM-1 and ␣v␤3 by cultured endothelium (125). Furthermore, it was shown that activation of NF␬B, which also regulates transcription of the
MCP-1 gene, was significantly increased in EC treated
with activated platelets by way of an IL-1-mediated mechanism.
Another aspect of the contribution of platelets to
lesion formation may be their essential role in thrombin
generation (for review, see Ref. 326). Furthermore, platelets upregulate tissue factor expression in monocytes in a
P-selectin-dependent reaction (195). Although the role of
thrombin in lesion formation is still debated, it has been
shown that patients with impaired thrombin generation
have reduced atherosclerosis (50). However, the very recent report by Sramek (492) found no link between decreased coagulability and atherogenesis based on observations in individuals with a hereditary bleeding tendency
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
may support recruitment of monocytes from the circulation to the endothelium, epitomizing a proximal step in an
emerging hierarchy (556). Platelet factor 4 (PF4) induces
upregulation of monocyte activation (141), firm adherence of neutrophils on shear stressed endothelium, and
release of neutrophil granule components (407).
In addition to the proinflammatory products mentioned above, two interleukin substances have been identified in platelets. A cell-associated form of IL-1␤ was
demonstrated on ADP- and epinephrine-activated platelets, active in inducing the expression of ICAM-1 and the
production of IL-6, IL-8, and GM-CSF by endothelial cells
(208, 251). Furthermore, epinephrine was found to upregulate IL-8 production in a platelet-dependent reaction
in LPS-stimulated blood (142).
A link between platelets and atherogenesis has been
suggested in studies demonstrating that platelets are activated by very low, physiologically relevant concentrations of oxygen free radicals generated chemically by
leukocytes (for a review, see Ref. 236). This could also be
part of the explanation why the white blood cell count,
which is a measure primarily of the numbers of granulocytes, proficient oxygen radical generating cells, is an
independent risk factor of CHD (108, 557).
One of the principal proinflammatory attributes of
platelets is their propensity for P-selectin exposure and
subsequent induction of various proinflammatory products. P-selectin is stored in the ␣-granules and is translocated to the platelet surface in an exocytotic process
comprising fusion of the ␣-granule membrane with the
platelet outer membrane. As mentioned earlier in this
review, exposed P-selectin will then interact with its ligand PSGL-1 on monocytes and neutrophils (for a review,
see Refs. 82, 111). Such binding has been shown to prime
PAF synthesis and phagocytosis in monocytes (140). An
ensuing activation of leukocytes has also been suggested,
since induction of TF in monocytes upon P-selectinPSGL-1 interaction has been reported (80). However,
other groups were not able to affirm this (383, 560).
Furthermore, P-selectin exposed on activated platelets
has been found to induce monocyte superoxide anion
production (530), NF␬B translocation, and secretion of
MCP-1 and monocyte IL-8 (560). In a whole blood system
it was shown that epinephrine upregulates IL-8 production in a platelet- and P-selectin-dependent reaction (142).
Recently it was reported that platelets contain the
CD40 ligand (CD40L) and that it is expressed on the
surface of activated platelets (212). Upon ligation, the
cognate receptor CD40, which is present on B cells,
monocytes, macrophages, and endothelial cells, may trigger inflammatory reactions (540). The ligation of endothelial CD40 to CD40L on activated platelets was shown to
induce adhesion molecule expression, chemokine secretion, and TF expression in endothelial cells (212, 487) and
monocytes (307).
MONOCYTES IN ATHEROGENESIS
X. CONCLUSIONS
The important role of monocytes in the early phase of
atherogenesis has been established through studies on
the regulation of their recruitment to the intima by adhesive molecules and chemokines that are essential to the
process. Because this process is initiated by LDL, the
monocyte activation and function is greatly influenced by
trapping of LDL in the vessel wall. New data emphasize
the role of the cellular inflammatory system associated
with the potential for oxidative lipoprotein modulation.
This process unfolds as an inflammatory response involving monocytes and macrophages in concert with lymphocytes and endothelial cells, crucial for the excessive macrophage consumption of oxidized LDL leading to foam
cell generation.
The importance of monocyte/macrophage activities
in atherogenesis has been explored through studies on
cellular signaling, notably pertaining to the roles of phospholipases, i.e., sPLA2 and cPLA2, and lipoxygenases,
which convert arachidonic acid into active oxidative metabolites, HETEs, and leukotrienes. Corroborative as well
as new evidence for many of the signal mechanisms that
are currently seen as playing a mandatory role in atherogenesis has been obtained from studies using transgenic
animals, particularly mice, systematically exploring the
effects of lesion formation of abolishing or overexpressing certain pathways. The emerging realization that
PPARs are involved in regulating the production and activities of activation products of monocytes/macrophages
Physiol Rev • VOL
such as oxidative metabolites, cytokines, and growth factors, gives further credence to the notion that these cells
have an important role in the development of fatty lesions.
The recent observation of polymorphism of the gene
of the CD14 receptor on monocytes/macrophages and
how it relates to myocardial infarction in individuals with
no other risk factor may provide a link for substantiating
the indications that chronic infections, particularly Chlamydia pneumonia, may enhance the development of atherosclerosis. Although not established, we hypothesize
that platelets may be playing an important role in the early
phase of atherogenesis through their proinflammatory
properties.
We are indepted to Prof. Leif Jørgensen for his review and
suggestions, and we express our gratitude to Dr. K. E. Eilertsen
for designing Figure 2.
Address for reprint requests and other correspondence: B.
Østerud, Dept. of Biochemistry, Institute of Medical Biology,
Faculty of Medicine, University of Tromsø, 9037 Tromsø, Norway (E-mail: [email protected]).
REFERENCES
1. Abraham R, Choudhury A, Basu SK, Bal V, and Rath S. Disruption of T cell tolerance by directing a self antigen to macrophage-specific scavenger receptors. J Immunol 158: 4029 – 4035,
1997.
2. Abramovitz M, Wong E, Cox ME, Richardson CD, Li C, and
Vickers PJ. 5-Lipoxygenase-activating protein stimulates the utilization of arachidonic acid by 5-lipoxygenase. Eur J Biochem 215:
105–111, 1993.
3. Adachi H, Tsujimoto M, Arai H, and Inoue K. Expression
cloning of a novel scavenger receptor from human endothelial
cells. J Biol Chem 272: 31217–31220, 1997.
4. Aggarwal BB and Natarajan K. Tumor necrosis factors: developments during the last decade. Eur Cytokine Netw 7: 93–124,
1996.
5. Aiello RJ, Bourassa PA, Lindsey S, Weng W, Freeman A, and
Showell HJ. Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice. Arterioscler Thromb Vasc Biol 22: 443–
449, 2002.
6. Aiello RJ, Bourassa PA, Lindsey S, Weng W, Natoli E, Rollins
BJ, and Milos PM. Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 19: 1518 –1525, 1999.
7. Akira S. The role of IL-18 in innate immunity. Curr Opin Immunol
12: 59 – 63, 2000.
8. Akira S, Hirano T, Taga T, and Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF).
FASEB J 4: 2860 –2867, 1990.
9. Allen S, Khan S, Al-Mohanna F, Batten P, and Yacoub M.
Native low density lipoprotein-induced calcium transients trigger
VCAM-1 and E-selectin expression in cultured human vascular
endothelial cells. J Clin Invest 101: 1064 –1075, 1998.
10. Ambrosio G, Oriente A, Napoli C, Palumbo G, Chiariello P,
Marone G, Condorelli M, Chiariello M, and Triggiani M. Oxygen radicals inhibit human plasma acetylhydrolase, the enzyme
that catabolizes platelet-activating factor. J Clin Invest 93: 2408 –
2416, 1994.
11. Annema A, Sluiter W, and van Furth R. Effect of interleukin 1,
macrophage colony-stimulating factor, and factor increasing monocytopoiesis on the production of leukocytes in mice. Exp Hematol
20: 69 –74, 1992.
12. Anthonsen MW, Stengel D, Hourton D, Ninio E, and Johansen
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
(hemophilia and/or von Willebrand disease). It was suggested that the protection against myocardial infarctions
that has been reported in hemophilia patients probably is
primarily caused by a decreased tendency to form occluding arterial thrombi.
Based on our own observation of an association between myocardial infarction and large platelets (large
mean platelet volume, MPV) in men aged 45– 65 years
belonging to a number of families with apparently inherited hyperactive platelets with large MPV, in the absence
of any other risk factors of CHD (68), and recent new data
linking platelets to lesion formation, we postulate that
platelets may play an important role not only in thrombus
formation at plaque rupture, but even in the early phase of
atherosclerosis.
We infer from the available data that the trait of
inheritable large platelets predisposes for early development of atherosclerosis and that this in turn is a reflection
of a pivotal role of platelets in atherogenesis. This hypothesis is corroborated by the recent documentation that
platelet-derived microparticles, which are enhanced in
large platelets (490), are capable of activating platelets as
well as monocytes and endothelial cells (37).
1097
1098
13.
14.
15.
16.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
B. Mildly oxidized LDL induces expression of group IIa secretory
phospholipase A (2) in human monocyte-derived macrophages.
Arterioscler Thromb Vasc Biol 20: 1276 –1282, 2000.
Apostolopoulos J, Davenport P, and Tipping PG. Interleukin-8
production by macrophages from atheromatous plaques. Arterioscler Thromb Vasc Biol 16: 1007–1012, 1996.
Arbustini E, Grasso M, Diegoli M, Pucci A, Bramerio M, Ardissino D, Angoli L, de Servi S, Bramucci E, Mussini A, Minzoni A, Vigano M, and Specchia G. Coronary atherosclerotic
plaques with and without thrombus in ischemic heart syndromes: a
morphologic, immunohistochemical, and biochemical study. Am J
Cardiol 68: 36B–50B, 1991.
Arend WP, Joslin FG, and Massoni RJ. Effects of immune
complexes on production by human monocytes of interleukin 1 or
an interleukin 1 inhibitor. J Immunol 134: 3868 –3875, 1985.
Arias-Negrete S, Keller K, and Chadee K. Proinflammatory
cytokines regulate cyclooxygenase-2 mRNA expression in human
macrophages. Biochem Biophys Res Commun 208: 582–589, 1995.
Arnaout MA. Leukocyte adhesion molecules deficiency: its structural basis, pathophysiology and implications for modulating the
inflammatory response. Immunol Rev 114: 145–180, 1990.
Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB,
Finberg RW, Koo GC, and Calderwood SK. HSP70 stimulates
cytokine production through a CD14-dependent pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:
435– 442, 2000.
Atkinson JB, Harlan CW, Harlan GC, and Virmani R. The
association of mast cells and atherosclerosis: a morphologic study
of early atherosclerotic lesions in young people. Hum Pathol 25:
154 –159, 1994.
Audoly LP, Rocca B, Fabre JE, Koller BH, Thomas D, Loeb
AL, Coffman TM, and FitzGerald GA. Cardiovascular responses
to the isoprostanes iPF (2alpha)-III and iPE (2)-III are mediated via
the thromboxane A (2) receptor in vivo. Circulation 101: 2833–
2840, 2000.
Auer JW, Berent R, Weber T, and Eber B. Immunopathogenesis
of atherosclerosis. Circulation 105: E64, 2002.
Aviram M. Does paraoxonase play a role in susceptibility to cardiovascular disease? Mol Med Today 5: 381–386, 1999.
Aviram M and Fuhrman B. Wine flavonoids protect against LDL
oxidation and atherosclerosis. Ann NY Acad Sci 957: 146 –161,
2002.
Aviram M, Kent UM, and Hollenberg PF. Microsomal cytochromes P450 catalyze the oxidation of low density lipoprotein.
Atherosclerosis 143: 253–260, 1999.
Bacon CM, Cho SS, and O’Shea JJ. Signal transduction by
interleukin-12 and interleukin-2. A comparison and contrast. Ann
NY Acad Sci 795: 41–59, 1996.
Badimon L, Badimon JJ, Chesebro JH, and Fuster V. von
Willebrand factor and cardiovascular disease. Thromb Haemost 70:
111–118, 1993.
Baggiolini M. Chemokines in pathology and medicine. J Intern
Med 250: 91–104, 2001.
Balboa MA, Balsinde J, Winstead MV, Tischfield JA, and Dennis EA. Novel group V phospholipase A2 involved in arachidonic
acid mobilization in murine P388D1 macrophages. J Biol Chem
271: 32381–32384, 1996.
Balsinde J, Balboa MA, Insel PA, and Dennis EA. Regulation
and inhibition of phospholipase A2. Annu Rev Pharmacol Toxicol
39: 175–189, 1999.
Balsinde J, Balboa MA, Li WH, Llopis J, and Dennis EA.
Cellular regulation of cytosolic group IV phospholipase A2 by phosphatidylinositol bisphosphate levels. J Immunol 164: 5398 –5402,
2000.
Balter MS, Toews GB, and Peters-Golden M. Different patterns
of arachidonate metabolism in autologous human blood monocytes
and alveolar macrophages. J Immunol 142: 602– 608, 1989.
Banchereau J, Briere F, Galizzi JP, Miossec P, and Rousset F.
Human interleukin 4. J Lipid Mediat Cell Signal 9: 43–53, 1994.
Bardot O, Aldridge TC, Latruffe N, and Green S. PPAR-RXR
heterodimer activates a peroxisome proliferator response element
upstream of the bifunctional enzyme gene. Biochem Biophys Res
Commun 192: 37– 45, 1993.
Physiol Rev • VOL
34. Barks JL, McQuillan JJ, and Iademarco MF. TNF-alpha and
IL-4 synergistically increase vascular cell adhesion molecule-1 expression in cultured vascular smooth muscle cells. J Immunol 159:
4532– 4538, 1997.
35. Baron JM, Zwadlo-Klarwasser G, Jugert F, Hamann W,
Rubben A, Mukhtar H, and Merk HF. Cytochrome P450 1B1: a
major P450 isoenzyme in human blood monocytes and macrophage
subsets. Biochem Pharmacol 56: 1105–1110, 1998.
36. Barry OP and FitzGerald GA. Mechanisms of cellular activation
by platelet microparticles. Thromb Haemost 82: 794 – 800, 1999.
37. Barry OP, Pratico D, Savani RC, and FitzGerald GA. Modulation of monocyte-endothelial cell interactions by platelet microparticles. J Clin Invest 102: 136 –144, 1998.
38. Bataille R, Jourdan M, Zhang XG, and Klein B. Serum levels of
interleukin 6, a potent myeloma cell growth factor, as a reflect of
disease severity in plasma cell dyscrasias. J Clin Invest 84: 2008 –
2011, 1989.
39. Bazan HE, Tao Y, and Bazan NG. Platelet-activating factor induces collagenase expression in corneal epithelial cells. Proc Natl
Acad Sci USA 90: 8678 – 8682, 1993.
40. Belch JJ. The relationship between white blood cells and arterial
disease. Curr Opin Lipidol 5: 440 – 446, 1994.
41. Belkner J, Wiesner R, Rathman J, Barnett J, Sigal E, and
Kuhn H. Oxygenation of lipoproteins by mammalian lipoxygenases. Eur J Biochem 213: 251–261, 1993.
42. Bellavite P. The superoxide-forming enzymatic system of phagocytes. Free Radic Biol Med 4: 225–261, 1988.
43. Benveniste J. PAF-acether, an ether phospho-lipid with biological
activity. Prog Clin Biol Res 282: 73– 85, 1988.
44. Benz DJ, Mol M, Ezaki M, Mori-Ito N, Zelan I, Miyanohara A,
Friedmann T, Parthasarathy S, Steinberg D, and Witztum JL.
Enhanced levels of lipoperoxides in low density lipoprotein incubated with murine fibroblast expressing high levels of human 15lipoxygenase. J Biol Chem 270: 5191–5197, 1995.
45. Berkhout TA, Sarau HM, Moores K, White JR, Elshourbagy N,
Appelbaum E, Reape RJ, Brawner M, Makwana J, Foley JJ,
Schmidt DB, Imburgia C, McNulty D, Matthews J, O’Donnell
K, O’Shannessy D, Scott M, Groot PHE, and Macphee C.
Cloning, in vitro expression, and functional characterization of a
novel human CC chemokine of the monocyte chemotactic protein
(MCP) family (MCP-4) that binds and signals through the CC
chemokine receptor 2B. J Biol Chem 272: 16404 –16413, 1997.
46. Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL,
Edwards PA, Watson AD, and Lusis AJ. Atherosclerosis: basic
mechanisms. Oxidation, inflammation, and genetics. Circulation
91: 2488 –2496, 1995.
47. Berliner JA, Territo MC, Sevanian A, Ramin S, Kim JA, Bamshad B, Esterson M, and Fogelman AM. Minimally modified low
density lipoprotein stimulates monocyte endothelial interactions.
J Clin Invest 85: 1260 –1266, 1990.
48. Bigby TD and Holtzman MJ. Enhanced 5-lipoxygenase activity in
lung macrophages compared to monocytes from normal subjects.
J Immunol 138: 1546 –1550, 1987.
49. Billiau A, Heremans H, Vermeire K, and Matthys P. Immunomodulatory properties of interferon-gamma. An update. Ann NY
Acad Sci 856: 22–32, 1998.
50. Bilora F, Dei Rossi C, Girolami B, Casonato A, Zanon E,
Bertomoro A, and Girolami A. Do hemophilia A and von Willebrand disease protect against carotid atherosclerosis? A comparative study between coagulopathics and normal subjects by means
of carotid echo-color Doppler scan. Clin Appl Thromb Hemost 5:
232–235, 1999.
51. Bingham CO III, Murakami M, Fujishima H, Hunt JE, Austen
KF, and Arm JP. A heparin-sensitive phospholipase A2 and prostaglandin endoperoxide synthase-2 are functionally linked in the
delayed phase of prostaglandin D2 generation in mouse bone marrow-derived mast cells. J Biol Chem 271: 25936 –25944, 1996.
52. Bober LA, Grace MJ, Pugliese-Sivo C, Rojas-Triana A, Sullivan LM, and Narula SK. The effects of colony stimulating factors
on human monocyte cell function. Int J Immunopharmacol 17:
385–392, 1995.
53. Bocan TM, Rosebury WS, Mueller SB, Kuchera S, Welch K,
Daugherty A, and Cornicelli JA. A specific 15-lipoxygenase in-
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
17.
BJARNE ØSTERUD AND EIRIK BJØRKLID
MONOCYTES IN ATHEROGENESIS
54.
55.
56.
57.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
Physiol Rev • VOL
73. Buchanan MR, Butt RW, Magas Z, van Ryn J, Hirsh J, and
Nazir DJ. Endothelial cells produce a lipoxygenase derived
chemo-repellent which influences platelet/endothelial cell interactions— effect of aspirin and salicylate. Thromb Haemost 53: 306 –
311, 1985.
74. Buchanan MR, Haas TA, Lagarde M, and Guichardant M.
13-Hydroxyoctadecadienoic acid is the vessel wall chemorepellant
factor, LOX. J Biol Chem 260: 16056 –16059, 1985.
75. Burgess AW and Metcalf D. The nature and action of granulocyte-macrophage colony stimulating factors. Blood 56: 947–958,
1980.
76. Burleigh ME, Babaev VR, Oates JA, Harris RC, Gautam S,
Riendeau D, Marnett LJ, Morrow JD, Fazio S, and Linton MF.
Cyclooxygenase-2 promotes early atherosclerotic lesion formation
in LDL receptor-deficient mice. Circulation 105: 1816 –1823, 2002.
77. Callaghan MM, Lovis RM, Rammohan C, Lu Y, and Pope RM.
Autocrine regulation of collagenase gene expression by TNF-alpha
in U937 cells. J Leukoc Biol 59: 125–132, 1996.
78. Cavaillon JM. Cytokines and macrophages. Biomed Pharmacother 48: 445– 453, 1994.
79. Cayatte AJ, Du Y, Oliver-Krasinski J, Lavielle G, Verbeuren
TJ, and Cohen RA. The thromboxane receptor antagonist S18886
but not aspirin inhibits atherogenesis in apo E-deficient mice:
evidence that eicosanoids other than thromboxane contribute to
atherosclerosis. Arterioscler Thromb Vasc Biol 20: 1724 –1728,
2000.
80. Celi A, Pellegrini G, Lorenzet R, De Blasi A, Ready N, Furie
BC, and Furie B. P-selectin induces the expression of tissue factor
on monocytes. Proc Natl Acad Sci USA 91: 8767– 8771, 1994.
81. Cerilli J, Brasile L, and Karmody A. Role of the vascular endothelial cell antigen system in the etiology of atherosclerosis. Ann
Surg 202: 329 –334, 1985.
82. Cerletti C, Evangelista V, and de Gaetano G. P-selectin-beta
2-integrin cross-talk: a molecular mechanism for polymorphonuclear leukocyte recruitment at the site of vascular damage. Thromb
Haemost 82: 787–793, 1999.
83. Cermak J, Key NS, Bach RR, Balla J, Jacob HS, and Vercellotti GM. C-reactive protein induces human peripheral blood
monocytes to synthesize tissue factor. Blood 82: 513–520, 1993.
84. Chait A and Wight TN. Interaction of native and modified lowdensity lipoproteins with extracellular matrix. Curr Opin Lipidol
11: 457– 463, 2000.
85. Chambon P. The molecular and genetic dissection of the retinoid
signaling pathway. Recent Prog Horm Res 50: 317–332, 1995.
86. Chan BM, Elices MJ, Murphy E, and Hemler ME. Adhesion to
vascular cell adhesion molecule 1 and fibronectin. Comparison of
alpha 4 beta 1 (VLA-4) and alpha 4 beta 7 on the human B cell line
JY. J Biol Chem 267: 8366 – 8370, 1992.
87. Chen Y, Morimoto S, Kitano S, Koh E, Fukuo K, Jiang B, Chen
S, Yasuda O, Hirotani A, and Ogihara T. Lysophosphatidylcholine causes Ca2⫹ influx, enhanced DNA synthesis and cytotoxicity
in cultured vascular smooth muscle cells. Atherosclerosis 112:
69 –76, 1995.
88. Chen YM, Wu KD, Tsai TJ, and Hsieh BS. Pentoxifylline inhibits
PDGF-induced proliferation of and TGF-beta-stimulated collagen
synthesis by vascular smooth muscle cells. J Mol Cell Cardiol 31:
773–783, 1999.
89. Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd
Z, Fruchart JC, Chapman J, Najib J, and Staels B. Activation of
proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem 273:
25573–25580, 1998.
90. Chisolm GM III, Hazen SL, Fox PL, and Cathcart MK. The
oxidation of lipoproteins by monocytes-macrophages. Biochemical
and biological mechanisms. J Biol Chem 274: 25959 –25962, 1999.
91. Christen S, Thomas SR, Garner B, and Stocker R. Inhibition by
interferon-gamma of human mononuclear cell-mediated low density lipoprotein oxidation. Participation of tryptophan metabolism
along the kynurenine pathway. J Clin Invest 93: 2149 –2158, 1994.
92. Chuluyan HE, Schall TJ, Yoshimura T, and Issekutz AC. IL-1
activation of endothelium supports VLA-4 (CD49d/CD29)-mediated
monocyte transendothelial migration to C5a, MIP-1 alpha,
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
58.
hibitor limits the progression and monocyte-macrophage enrichment of hypercholesterolemia-induced atherosclerosis in the rabbit. Atherosclerosis 136: 203–216, 1998.
Boerboom LE, Olinger GN, Almassi GH, and Skrinska VA.
Both dietary fish-oil supplementation and aspirin fail to inhibit
atherosclerosis in long-term vein bypass grafts in moderately hypercholesterolemic nonhuman primates. Circulation 96: 968 –974,
1997.
Bogdan C and Nathan C. Modulation of macrophage function by
transforming growth factor beta, interleukin-4, and interleukin-10.
Ann NY Acad Sci 685: 713–739, 1993.
Boisvert WA, Curtiss LK, and Terkeltaub RA. Interleukin-8 and
its receptor CXCR2 in atherosclerosis. Immunol Res 21: 129 –137,
2000.
Bonavida B, Mencia-Huerta JM, and Braquet P. Effect of platelet-activating factor on monocyte activation and production of
tumor necrosis factor. Int Arch Allergy Appl Immunol 88: 157–160,
1989.
Bonavida B, Mencia-Huerta JM, and Braquet P. Effects of
platelet-activating factor on peripheral blood monocytes: induction
and priming for TNF secretion. J Lipid Mediat 2: S65–S76, 1990.
Bonta IL, Adolfs MJ, and Fieren MW. Cyclic AMP levels and
their regulation by prostaglandins in peritoneal macrophages of
rats and humans. Int J Immunopharmacol 6: 547–555, 1984.
Bonventre JV, Huang Z, Taheri MR, O’Leary E, Li E, Moskowitz MA, and Sapirstein A. Reduced fertility and postischaemic
brain injury in mice deficient in cytosolic phospholipase A2. Nature
390: 622– 625, 1997.
Borgeat P, Hamberg M, and Samuelsson B. Transformation of
arachidonic acid and homo-gamma-linolenic acid by rabbit polymorphonuclear leukocytes. Monohydroxy acids from novel lipoxygenases. J Biol Chem 251: 7816 –7820, 1976.
Boring L, Gosling J, Cleary M, and Charo IF. Decreased lesion
formation in CCR2⫺/⫺ mice reveals a role for chemokines in the
initiation of atherosclerosis. Nature 394: 894 – 897, 1998.
Bradding P, Redington AE, Djukanovic R, Conrad DJ, and
Holgate ST. 15-Lipoxygenase immunoreactivity in normal and in
asthmatic airways. Am J Respir Crit Care Med 151: 1201–1204,
1995.
Braissant O, Foufelle F, Scotto C, Dauca M, and Wahli W.
Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma
in the adult rat. Endocrinology 137: 354 –366, 1996.
Brand K, Banka CL, Mackman N, Terkeltaub RA, Fan ST, and
Curtiss LK. Oxidized LDL enhances lipopolysaccharide-induced
tissue factor expression in human adherent monocytes. Arterioscler Thromb 14: 790 –797, 1994.
Brandwein SR. Regulation of interleukin 1 production by mouse
peritoneal macrophages. Effects of arachidonic acid metabolites,
cyclic nucleotides, and interferons. J Biol Chem 261: 8624 – 8632,
1986.
Bray MA, McKearn-Smith C, Metz-Virca G, Bodmer JL, and
Virca GD. Stimulated release of neutral proteinases elastase and
cathepsin G from inflammatory rat polymorphonuclear leukocytes.
Inflammation 11: 23–37, 1987.
Breimo ES and Østerud B. Characterization of platelets in patients with inherited large platelet syndrome. In: Vasular Protection, Molecular Mechanisms, Novel Therapeutic Principles and
Clinical Application, edited by Rubanyi G, Dzau V, and Cooke J.
New York: Taylor & Francis, 2002, p. 359 –367.
Breyer MD, Jacobson HR, and Breyer RM. Functional and
molecular aspects of renal prostaglandin receptors. J Am Soc
Nephrol 7: 8 –17, 1996.
Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT,
Bleharski JR, Maitland M, Norgard MV, Plevy SE, Smale ST,
Brennan PJ, Bloom BR, Godowski PJ, and Modlin RL. Host
defense mechanisms triggered by microbial lipoproteins through
toll-like receptors. Science 285: 732–736, 1999.
Brohee D and Higuet N. In vitro stimulation of peripheral blood
mononuclear cells by phytohaemagglutinin A induces CD45RA expression on monocytes. Cytobios 71: 105–111, 1992.
Brown MS and Goldstein JL. A receptor-mediated pathway for
cholesterol homeostasis. Science 232: 34 – 47, 1986.
1099
1100
93.
94.
95.
96.
97.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
RANTES, and PAF but inhibits migration to MCP-1: a regulatory
role for endothelium-derived MCP-1. J Leukoc Biol 58: 71–79, 1995.
Clinton SK, Fleet JC, Loppnow H, Salomon RN, Clark BD,
Cannon JG, Shaw AR, Dinarello CA, and Libby P. Interleukin-1
gene expression in rabbit vascular tissue in vivo. Am J Pathol 138:
1005–1014, 1991.
Colten H, Cole F, Sackstein R, and Auerbach H. Tissue and
Specific Regulation of Complement Biosynthesis in Mononuclear
Phagocytes. Dordrecht, Germany: Martinus Nijhoff Publishers,
1985.
Colville-Nash PR, Qureshi SS, Willis D, and Willoughby DA.
Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists: correlation with induction of
heme oxygenase 1. J Immunol 161: 978 –984, 1998.
Conner EM and Grisham MB. Inflammation, free radicals, and
antioxidants. Nutrition 12: 274 –277, 1996.
Conrad DJ, Kuhn H, Mulkins M, Highland E, and Sigal E.
Specific inflammatory cytokines regulate the expression of human
monocyte 15-lipoxygenase. Proc Natl Acad Sci USA 89: 217–221,
1992.
Cornhill JF and Roach MR. Quantitative method for the evaluation of atherosclerotic lesions. Atherosclerosis 20: 131–136, 1974.
Cornicelli JA, Butteiger D, Rateri DL, Welch K, and Daugherty A. Interleukin-4 augments acetylated LDL-induced cholesterol
esterification in macrophages. J Lipid Res 41: 376 –383, 2000.
Cornicelli JA and Trivedi BK. 15-Lipoxygenase and its inhibition: a novel therapeutic target for vascular disease. Curr Pharm
Des 5: 11–20, 1999.
Cornicelli JA, Welch K, Auerbach B, Feinmark SJ, and Daugherty A. Mouse peritoneal macrophages contain abundant omega-6
lipoxygenase activity that is independent of interleukin-4. Arterioscler Thromb Vasc Biol 16: 1488 –1494, 1996.
Creemers EE, Cleutjens JP, Smits JF, and Daemen MJ. Matrix
metalloproteinase inhibition after myocardial infarction: a new
approach to prevent heart failure? Circ Res 89: 201–210, 2001.
Crooks SW and Stockley RA. Leukotriene B4. Int J Biochem Cell
Biol 30: 173–178, 1998.
Cunard R, Ricote M, DiCampli D, Archer DC, Kahn DA, Glass
CK, and Kelly CJ. Regulation of cytokine expression by ligands of
peroxisome proliferator activated receptors. J Immunol 168: 2795–
2802, 2002.
Cushing SD, Berliner JA, Valente AJ, Territo MC, Navab M,
Parhami F, Gerrity R, Schwartz CJ, and Fogelman AM. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle
cells. Proc Natl Acad Sci USA 87: 5134 –5138, 1990.
Cyrus T, Pratico D, Zhao L, Witztum JL, Rader DJ, Rokach J,
FitzGerald GA, and Funk CD. Absence of 12/15-lipoxygenase
expression decreases lipid peroxidation and atherogenesis in apolipoprotein E-deficient mice. Circulation 103: 2277–2282, 2001.
Cyrus T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton
MF, and Funk CD. Disruption of the 12/15-lipoxygenase gene
diminishes atherosclerosis in apo E-deficient mice. J Clin Invest
103: 1597–1604, 1999.
Danesh J, Collins R, Appleby P, and Peto R. Association of
fibrinogen, C-reactive protein, albumin, or leukocyte count with
coronary heart disease: meta-analyses of prospective studies.
JAMA 279: 1477–1482, 1998.
Danesh J, Collins R, and Peto R. Chronic infections and coronary heart disease: is there a link? Lancet 350: 430 – 436, 1997.
Dawson TC, Kuziel WA, Osahar TA, and Maeda N. Absence of
CC chemokine receptor-2 reduces atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 143: 205–211, 1999.
De Gaetano G, Cerletti C, and Evangelista V. Recent advances
in platelet-polymorphonuclear leukocyte interaction. Haemostasis
29: 41– 49, 1999.
Delerive P, De Bosscher K, Besnard S, Vanden Berghe W,
Peters JM, Gonzalez FJ, Fruchart JC, Tedgui A, Haegeman G,
and Staels B. Peroxisome proliferator-activated receptor alpha
negatively regulates the vascular inflammatory gene response by
negative cross-talk with transcription factors NF-kappaB and AP-1.
J Biol Chem 274: 32048 –32054, 1999.
De Martin R, Hoeth M, Hofer-Warbinek R, and Schmid JA. The
Physiol Rev • VOL
114.
115.
116.
117.
118.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
transcription factor NF-kappa B and the regulation of vascular cell
function. Arterioscler Thromb Vasc Biol 20: E83–E88, 2000.
De Meyer GR, Hoylaerts MF, Kockx MM, Yamamoto H, Herman AG, and Bult H. Intimal deposition of functional von Willebrand factor in atherogenesis. Arterioscler Thromb Vasc Biol 19:
2524 –2534, 1999.
Dentan C, Lesnik P, Chapman MJ, and Ninio E. Phagocytic
activation induces formation of platelet-activating factor in human
monocyte-derived macrophages and in macrophage-derived foam
cells. Relevance to the inflammatory reaction in atherogenesis. Eur
J Biochem 236: 48 –55, 1996.
Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ,
and Wahli W. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 384: 39 – 43, 1996.
Devlin CM, Kuriakose G, Hirsch E, and Tabas I. Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol
level and foam cell lesion size. Proc Natl Acad Sci USA 99: 6280 –
6285, 2002.
De Winther MP, Gijbels MJ, van Dijk KW, van Gorp PJ,
Suzuki H, Kodama T, Frants RR, Havekes LM, and Hofker
MH. Scavenger receptor deficiency leads to more complex atherosclerotic lesions in APOE3Leiden transgenic mice. Atherosclerosis
144: 315–321, 1999.
Dhaliwal BS and Steinbrecher UP. Scavenger receptors and
oxidized low density lipoproteins. Clin Chim Acta 286: 191–205,
1999.
Diamond P, McGinty A, Sugrue D, Brady HR, and Godson C.
Regulation of leukocyte trafficking by lipoxins. Clin Chem Lab Med
37: 293–297, 1999.
Diaz B and Lopez-Berestein G. A distinct element involved in
lipopolysaccharide activation of the tumor necrosis factor-alpha
promoter in monocytes. J Interferon Cytokine Res 20: 741–748,
2000.
Diaz MN, Frei B, Vita JA, and Keaney JF Jr. Antioxidants and
atherosclerotic heart disease. N Engl J Med 337: 408 – 416, 1997.
DiChiara MR, Kiely JM, Gimbrone MA Jr, Lee ME, Perrella
MA, and Topper JN. Inhibition of E-selectin gene expression by
transforming growth factor beta in endothelial cells involves coactivator integration of Smad and nuclear factor kappaB-mediated
signals. J Exp Med 192: 695–704, 2000.
Dickfeld T, Lengyel E, May AE, Massberg S, Brand K, Page S,
Thielen C, Langenbrink K, and Gawaz M. Transient interaction
of activated platelets with endothelial cells induces expression of
monocyte-chemoattractant protein-1 via a p38 mitogen-activated
protein kinase mediated pathway. Implications for atherogenesis.
Cardiovasc Res 49: 189 –199, 2001.
Dietert RR and Golemboski KA. Avian macrophage metabolism.
Poult Sci 77: 990 –997, 1998.
Dinarello CA. Interleukin-1 and its biologically related cytokines.
Adv Immunol 44: 153–205, 1989.
Dinarello CA, Cannon JG, Wolff SM, Bernheim HA, Beutler B,
Cerami A, Figari IS, Palladino MA Jr, and O’Connor JV.
Tumor necrosis factor (cachectin) is an endogenous pyrogen and
induces production of interleukin 1. J Exp Med 163: 1433–1450,
1986.
Dindzans VJ, MacPhee PJ, Fung LS, Leibowitz JL, and Levy
GA. The immune response to mouse hepatitis virus: expression of
monocyte procoagulant activity and plasminogen activator during
infection in vivo. J Immunol 135: 4189 – 4197, 1985.
Djellas Y, Antonakis K, and Le Breton GC. A molecular mechanism for signaling between seven-transmembrane receptors: evidence for a redistribution of G proteins. Proc Natl Acad Sci USA 95:
10944 –10948, 1998.
Dogne JM, de Leval X, Delarge J, David JL, and Masereel B.
New trends in thromboxane and prostacyclin modulators. Curr
Med Chem 7: 609 – 628, 2000.
Dong ZM, Brown AA, and Wagner DD. Prominent role of Pselectin in the development of advanced atherosclerosis in ApoEdeficient mice. Circulation 101: 2290 –2295, 2000.
Dong ZM, Chapman SM, Brown AA, Frenette PS, Hynes RO,
and Wagner DD. The combined role of P- and E-selectins in
atherosclerosis. J Clin Invest 102: 145–152, 1998.
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
98.
BJARNE ØSTERUD AND EIRIK BJØRKLID
MONOCYTES IN ATHEROGENESIS
Physiol Rev • VOL
154.
155.
156.
157.
158.
159.
160.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
of a human cDNA encoding a functional high affinity lipoxin A4
receptor. J Exp Med 180: 253–260, 1994.
Fitzpatrick FA, Lepley R, Orning L, and Duffin K. Effects of
leukotriene A4 on neutrophil activation. Ann NY Acad Sci 714:
64 –74, 1994.
Folcik VA, Aamir R, and Cathcart MK. Cytokine modulation of
LDL oxidation by activated human monocytes. Arterioscler
Thromb Vasc Biol 17: 1954 –1961, 1997.
Forman BM, Chen J, and Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome
proliferator-activated receptors alpha and delta. Proc Natl Acad Sci
USA 94: 4312– 4317, 1997.
Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM,
and Evans RM. 15-Deoxy-delta 12,14-prostaglandin J2 is a ligand
for the adipocyte determination factor PPAR gamma. Cell 83: 803–
812, 1995.
Fouda SI, Molski TF, Ashour MS, and Sha’afi RI. Effect of
lipopolysaccharide on mitogen-activated protein kinases and cytosolic phospholipase A2. Biochem J 308: 815– 822, 1995.
Fourcin M, Chevalier S, Lebrun JJ, Kelly P, Pouplard A,
Wijdenes J, and Gascan H. Involvement of gp130/interleukin-6
receptor transducing component in interleukin-11 receptor. Eur
J Immunol 24: 277–280, 1994.
Frostegard J, Huang YH, Ronnelid J, and Schafer-Elinder L.
Platelet-activating factor and oxidized LDL induce immune activation by a common mechanism. Arterioscler Thromb Vasc Biol 17:
963–968, 1997.
Furie B, Furie BC, and Flaumenhaft R. A journey with platelet
P-selectin: the molecular basis of granule secretion, signalling and
cell adhesion. Thromb Haemost 86: 214 –221, 2001.
Furstenberger G, Hagedorn H, Jacobi T, Besemfelder E,
Stephan M, Lehmann WD, and Marks F. Characterization of an
8-lipoxygenase activity induced by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate in mouse skin in vivo.
J Biol Chem 266: 15738 –15745, 1991.
Fuster V and Griggs TR. Porcine von Willebrand disease: implications for the pathophysiology of atherosclerosis and thrombosis.
Prog Hemost Thromb 8: 159 –183, 1986.
Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E,
Unemori EN, Lark MW, Amento E, and Libby P. Cytokinestimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion.
Circ Res 75: 181–189, 1994.
Galis ZS, Sukhova GK, Lark MW, and Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin
Invest 94: 2493–2503, 1994.
Gearing DP, Comeau MR, Friend DJ, Gimpel SD, Thut CJ,
McGourty J, Brasher KK, King JA, Gillis S, Mosley B, Ziegler
SF, and Cosman D. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science
255: 1434 –1437, 1992.
Gearing KL, Gottlicher M, Teboul M, Widmark E, and
Gustafsson JA. Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor. Proc Natl Acad Sci USA 90:
1440 –1444, 1993.
Geng YJ, Holm J, Nygren S, Bruzelius M, Stemme S, and
Hansson GK. Expression of the macrophage scavenger receptor in
atheroma. Relationship to immune activation and the T-cell cytokine interferon-gamma. Arterioscler Thromb Vasc Biol 15: 1995–
2002, 1995.
Geng YJ and Libby P. Evidence for apoptosis in advanced human
atheroma. Colocalization with interleukin-1 beta-converting enzyme. Am J Pathol 147: 251–266, 1995.
Geng YJ, Wu Q, Muszynski M, Hansson GK, and Libby P.
Apoptosis of vascular smooth muscle cells induced by in vitro
stimulation with interferon-gamma, tumor necrosis factor-alpha,
and interleukin-1 beta. Arterioscler Thromb Vasc Biol 16: 19 –27,
1996.
George J, Mulkins M, Shaish A, Casey S, Schatzman R, Sigal
E, and Harats D. Interleukin (IL)-4 deficiency does not influence
fatty streak formation in C57BL/6 mice. Atherosclerosis 153: 403–
411, 2000.
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
134. Duguid J. Thrombosis as a factor in the pathogenesis of coronary
atherosclerosis. J Pathol Bacteriol 58: 207–212, 1946.
135. Eilertsen KE and Østerud B. The central role of thromboxane
and platelet activating factor receptors in ex vivo regulation of
endotoxin-induced monocyte tissue factor activity in human whole
blood. J Endotoxin Res 8: 285–293, 2002.
136. Elhage R, Maret A, Pieraggi MT, Thiers JC, Arnal JF, and
Bayard F. Differential effects of interleukin-1 receptor antagonist
and tumor necrosis factor binding protein on fatty-streak formation
in apolipoprotein E-deficient mice. Circulation 97: 242–244, 1998.
137. Eliassen LT, Rekdal O, Svendsen JS, and Østerud B. TNF
41– 62 and TNF 78 –96 have distinct effects on LPS-induced tissue
factor activity and the production of cytokines in human blood
cells. Thromb Haemost 83: 598 – 604, 2000.
138. Elices MJ, Osborn L, Takada Y, Crouse C, Luhowskyj S,
Hemler ME, and Lobb RR. VCAM-1 on activated endothelium
interacts with the leukocyte integrin VLA-4 at a site distinct from
the VLA-4/fibronectin binding site. Cell 60: 577–584, 1990.
139. Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P,
Katsikis P, Brennan FM, Walker J, Bijl H, Ghrayeb J, and
Woody JN. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum
36: 1681–1690, 1993.
140. Elstad MR, La Pine TR, Cowley FS, McEver RP, McIntyre TM,
Prescott SM, and Zimmerman GA. P-selectin regulates plateletactivating factor synthesis and phagocytosis by monocytes. J Immunol 155: 2109 –2122, 1995.
141. Engstad CS, Lia K, Rekdal O, Olsen JO, and Østerud B. A
novel biological effect of platelet factor 4 (PF4): enhancement of
LPS-induced tissue factor activity in monocytes. J Leukoc Biol 58:
575–581, 1995.
142. Engstad CS, Lund T, and Østerud B. Epinephrine promotes IL-8
production in human leukocytes via an effect on platelets. Thromb
Haemost 81: 139 –145, 1999.
143. Eriksson EE, Xie X, Werr J, Thoren P, and Lindbom L. Direct
viewing of atherosclerosis in vivo: plaque invasion by leukocytes is
initiated by the endothelial selectins. FASEB J 15: 1149 –1157, 2001.
144. Ernofsson M and Siegbahn A. Platelet-derived growth factor-BB
and monocyte chemotactic protein-1 induce human peripheral
blood monocytes to express tissue factor. Thromb Res 83: 307–320,
1996.
145. Essner R, Rhoades K, McBride WH, Morton DL, and Economou JS. Differential effects of granulocyte-macrophage colonystimulating factor and macrophage colony-stimulating factor on
tumor necrosis factor and interleukin-1 production in human
monocytes. J Clin Lab Immunol 32: 161–166, 1990.
146. Esterbauer H, Dieber-Rotheneder M, Striegl G, and Waeg G.
Role of vitamin E in preventing the oxidation of low-density lipoprotein. Am J Clin Nutr 53: 314S–321S, 1991.
147. Falcone DJ, McCaffrey TA, and Vergilio JA. Stimulation of
macrophage urokinase expression by polyanions is protein kinase
C-dependent and requires protein and RNA synthesis. J Biol Chem
266: 22726 –22732, 1991.
148. Fan J, Unoki H, Iwasa S, and Watanabe T. Role of endothelin-1
in atherosclerosis. Ann NY Acad Sci 902: 84 –93, 2000.
149. Fassina G, Ferrari N, Brigati C, Benelli R, Santi L, Noonan
DM, and Albini A. Tissue inhibitors of metalloproteases: regulation and biological activities. Clin Exp Metastasis 18: 111–120,
2000.
150. Febbraio M, Podrez EA, Smith JD, Hajjar DP, Hazen SL, Hoff
HF, Sharma K, and Silverstein RL. Targeted disruption of the
class B scavenger receptor CD36 protects against atherosclerotic
lesion development in mice. J Clin Invest 105: 1049 –1056, 2000.
151. Ferrante JV, Huang ZH, Nandoskar M, Hii CS, Robinson BS,
Rathjen DA, Poulos A, Morris CP, and Ferrante A. Altered
responses of human macrophages to lipopolysaccharide by hydroperoxy eicosatetraenoic acid, hydroxy eicosatetraenoic acid,
and arachidonic acid. Inhibition of tumor necrosis factor production. J Clin Invest 99: 1445–1452, 1997.
152. Filep JG, Delalandre A, Payette Y, and Foldes-Filep E. Glucocorticoid receptor regulates expression of L-selectin and CD11/
CD18 on human neutrophils. Circulation 96: 295–301, 1997.
153. Fiore S, Maddox JF, Perez HD, and Serhan CN. Identification
1101
1102
BJARNE ØSTERUD AND EIRIK BJØRKLID
Physiol Rev • VOL
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
207.
208.
209.
210.
211.
212.
Klaucke J, Poppelmann M, Becker WM, Gabius HJ, and
Schlaak M. Dietary lectins can induce in vitro release of IL-4 and
IL-13 from human basophils. Eur J Immunol 29: 918 –927, 1999.
Haas TA, Bastida E, Nakamura K, Hullin F, Admirall L, and
Buchanan MR. Binding of 13-HODE and 5-, 12- and 15-HETE to
endothelial cells and subsequent platelet, neutrophil and tumor cell
adhesion. Biochim Biophys Acta 961: 153–159, 1988.
Hajjar KA, Gavish D, Breslow JL, and Nachman RL. Lipoprotein (a) modulation of endothelial cell surface fibrinolysis and its
potential role in atherosclerosis. Nature 339: 303–305, 1989.
Halvorsen H, Olsen JO, and Østerud B. Granulocytes enhance
LPS-induced tissue factor activity in monocytes via an interaction
with platelets. J Leukoc Biol 54: 275–282, 1993.
Hamanaka R, Kohno K, Seguchi T, Okamura K, Morimoto A,
Ono M, Ogata J, and Kuwano M. Induction of low density
lipoprotein receptor and a transcription factor SP-1 by tumor necrosis factor in human microvascular endothelial cells. J Biol
Chem 267: 13160 –13165, 1992.
Hamberg M and Hamberg G. On the mechanism of the oxygenation of arachidonic acid by human platelet lipoxygenase. Biochem
Biophys Res Commun 95: 1090 –1097, 1980.
Hamberg M and Samuelsson B. On the specificity of the oxygenation of unsaturated fatty acids catalyzed by soybean lipoxidase.
J Biol Chem 242: 5329 –5335, 1967.
Hamilton JA, Myers D, Jessup W, Cochrane F, Byrne R,
Whitty G, and Moss S. Oxidized LDL can induce macrophage
survival, DNA synthesis, and enhanced proliferative response to
CSF-1 and GM-CSF. Arterioscler Thromb Vasc Biol 19: 98 –105,
1999.
Hammerschmidt DE, Kotasek D, McCarthy T, Huh PW, Freyburger G, and Vercellotti GM. Pentoxifylline inhibits granulocyte and platelet function, including granulocyte priming by platelet activating factor. J Lab Clin Med 112: 254 –263, 1988.
Han J, Hajjar DP, Febbraio M, and Nicholson AC. Native and
modified low density lipoproteins increase the functional expression of the macrophage class B scavenger receptor, CD36. J Biol
Chem 272: 21654 –21659, 1997.
Han J and Nicholson AC. Lipoproteins modulate expression of
the macrophage scavenger receptor. Am J Pathol 152: 1647–1654,
1998.
Hansson A, Serhan CN, Haeggstrom J, Ingelman-Sundberg M,
and Samuelsson B. Activation of protein kinase C by lipoxin A
and other eicosanoids. Intracellular action of oxygenation products
of arachidonic acid. Biochem Biophys Res Commun 134: 1215–
1222, 1986.
Hart PH, Bonder CS, Balogh J, Dickensheets HL, Donnelly
RP, and Finlay-Jones JJ. Differential responses of human monocytes and macrophages to IL-4 and IL-13. J Leukoc Biol 66: 575–578,
1999.
Hartwell DW and Wagner DD. New discoveries with mice mutant
in endothelial and platelet selectins. Thromb Haemost 82: 850 – 857,
1999.
Haskill S, Johnson C, Eierman D, Becker S, and Warren K.
Adherence induces selective mRNA expression of monocyte mediators and proto-oncogenes. J Immunol 140: 1690 –1694, 1988.
Hatada EN, Krappmann D, and Scheidereit C. NF-kappaB and
the innate immune response. Curr Opin Immunol 12: 52–58, 2000.
Hawrylowicz CM, Howells GL, and Feldmann M. Platelet-derived interleukin 1 induces human endothelial adhesion molecule
expression and cytokine production. J Exp Med 174: 785–790, 1991.
Hayek T, Oiknine J, Brook JG, and Aviram M. Role of HDL
apolipoprotein E in cellular cholesterol efflux: studies in apo E
knockout transgenic mice. Biochem Biophys Res Commun 205:
1072–1078, 1994.
Hayes AL, Smith C, Foxwell BM, and Brennan FM. CD45induced tumor necrosis factor alpha production in monocytes is
phosphatidylinositol 3-kinase-dependent and nuclear factorkappaB-independent. J Biol Chem 274: 33455–33461, 1999.
Heldin CH and Westermark B. Mechanism of action and in vivo
role of platelet-derived growth factor. Physiol Rev 79: 1283–1316,
1999.
Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R,
Muller-Berghaus G, and Kroczek RA. CD40 ligand on activated
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
173. George J, Shoenfeld Y, Afek A, Gilburd B, Keren P, Shaish A,
Kopolovic J, Wick G, and Harats D. Enhanced fatty streak
formation in C57BL/6J mice by immunization with heat shock
protein-65. Arterioscler Thromb Vasc Biol 19: 505–510, 1999.
174. George SJ. Tissue inhibitors of metalloproteinases and metalloproteinases in atherosclerosis. Curr Opin Lipidol 9: 413– 423, 1998.
175. Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding
HA, Gimbrone MA Jr, Luster AD, Luscinskas FW, and Rosenzweig A. MCP-1 and IL-8 trigger firm adhesion of monocytes to
vascular endothelium under flow conditions. Nature 398: 718 –723,
1999.
176. Glaser KB, Asmis R, and Dennis EA. Bacterial lipopolysaccharide priming of P388D1 macrophage-like cells for enhanced arachidonic acid metabolism. Platelet-activating factor receptor activation and regulation of phospholipase A2. J Biol Chem 265: 8658 –
8664, 1990.
177. Glover S, de Carvalho MS, Bayburt T, Jonas M, Chi E, Leslie
CC, and Gelb MH. Translocation of the 85-kDa phospholipase A2
from cytosol to the nuclear envelope in rat basophilic leukemia
cells stimulated with calcium ionophore or IgE/antigen. J Biol
Chem 270: 15359 –15367, 1995.
178. Goldman DW and Goetzl EJ. Specific binding of leukotriene B4
to receptors on human polymorphonuclear leukocytes. J Immunol
129: 1600 –1604, 1982.
179. Gomez-Munoz A, Martens JS, and Steinbrecher UP. Stimulation of phospholipase D activity by oxidized LDL in mouse peritoneal macrophages. Arterioscler Thromb Vasc Biol 20: 135–143,
2000.
180. Goodwin JS, Gualde N, Aldigier J, Rigaud M, and Vanderhoek
JY. Modulation of Fc gamma receptors on I cells and monocytes by
15 hydroperoxyeicosatetranoic acid. Prostaglandins Leukotrienes
Med 13: 109 –112, 1984.
181. Gosling J, Slaymaker S, Gu L, Tseng S, Zlot CH, Young SG,
Rollins BJ, and Charo IF. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest 103: 773–778, 1999.
182. Gough PJ, Greaves DR, Suzuki H, Hakkinen T, Hiltunen MO,
Turunen M, Herttuala SY, Kodama T, and Gordon S. Analysis
of macrophage scavenger receptor (SR-A) expression in human
aortic atherosclerotic lesions. Arterioscler Thromb Vasc Biol 19:
461– 471, 1999.
183. Goyert SM, Ferrero E, Rettig WJ, Yenamandra AK, Obata F,
and Le Beau MM. The CD14 monocyte differentiation antigen
maps to a region encoding growth factors and receptors. Science
239: 497–500, 1988.
184. Grage-Griebenow E, Lorenzen D, Fetting R, Flad HD, and
Ernst M. Phenotypical and functional characterization of Fc
gamma receptor I (CD64)-negative monocytes, a minor human
monocyte subpopulation with high accessory and antiviral activity.
Eur J Immunol 23: 3126 –3135, 1993.
185. Grainger DJ, Mosedale DE, and Metcalfe JC. TGF-beta in
blood: a complex problem. Cytokine Growth Factor Rev 11: 133–
145, 2000.
186. Griendling KK and Alexander RW. Oxidative stress and cardiovascular disease. Circulation 96: 3264 –3265, 1997.
187. Griswold DE and Adams JL. Constitutive cyclooxygenase
(COX-1) and inducible cyclooxygenase (COX-2): rationale for selective inhibition and progress to date. Med Res Rev 16: 181–206,
1996.
188. Grossman RM, Krueger J, Yourish D, Granelli-Piperno A,
Murphy DP, May LT, Kupper TS, Sehgal PB, and Gottlieb AB.
Interleukin 6 is expressed in high levels in psoriatic skin and
stimulates proliferation of cultured human keratinocytes. Proc Natl
Acad Sci USA 86: 6367– 6371, 1989.
189. Guan JL and Hynes RO. Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor alpha
4 beta 1. Cell 60: 53– 61, 1990.
190. Guha M and Mackman N. LPS induction of gene expression in
human monocytes. Cell Signal 13: 85–94, 2001.
191. Gupta S, Pablo AM, Jiang X, Wang N, Tall AR, and Schindler
C. IFN-gamma potentiates atherosclerosis in ApoE knock-out
mice. J Clin Invest 99: 2752–2761, 1997.
192. Haas H, Falcone FH, Schramm G, Haisch K, Gibbs BF,
MONOCYTES IN ATHEROGENESIS
213.
214.
215.
216.
217.
219.
221.
222.
223.
224.
225.
226.
227.
228.
229.
230.
231.
232.
Physiol Rev • VOL
233.
234.
235.
236.
237.
238.
239.
240.
241.
242.
243.
244.
245.
246.
247.
248.
249.
250.
J, Watanabe Y, Kawamura M, Yazaki Y, and Yamada N. Expression of platelet-derived growth factor beta receptor on human
monocyte-derived macrophages and effects of platelet-derived
growth factor BB dimer on the cellular function. J Biol Chem 268:
24353–24360, 1993.
Ip NY, Nye SH, Boulton TG, Davis S, Taga T, Li Y, Birren SJ,
Yasukawa K, Kishimoto T, Anderson DJ, Stahl N, and Yancopoulus GD. CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor
component gp130. Cell 69: 1121–1132, 1992.
Issemann I, Prince RA, Tugwood JD, and Green S. The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic
drugs. J Mol Endocrinol 11: 37– 47, 1993.
Ito D, Murata M, Tanahashi N, Sato H, Sonoda A, Saito I,
Watanabe K, and Fukuuchi Y. Polymorphism in the promoter of
lipopolysaccharide receptor CD14 and ischemic cerebrovascular
disease. Stroke 31: 2661–2664, 2000.
Iuliano L, Colavita AR, Leo R, Pratico D, and Violi F. Oxygen
free radicals and platelet activation. Free Radic Biol Med 22: 999 –
1006, 1997.
Ivandic B, Castellani LW, Wang XP, Qiao JH, Mehrabian M,
Navab M, Fogelman AM, Grass DS, Swanson ME, de Beer MC,
de Beer F, and Lusis AJ. Role of group II secretory phospholipase
A2 in atherosclerosis. 1. Increased atherogenesis and altered lipoproteins in transgenic mice expressing group IIa phospholipase
A2. Arterioscler Thromb Vasc Biol 19: 1284 –1290, 1999.
Jarrold BB, Bacon WL, and Velleman SG. Expression and localization of the proteoglycan decorin during the progression of
cholesterol induced atherosclerosis in Japanese quail: implications
for interaction with collagen type I and lipoproteins. Atherosclerosis 146: 299 –308, 1999.
Jiang C, Ting AT, and Seed B. PPAR-gamma agonists inhibit
production of monocyte inflammatory cytokines. Nature 391: 82–
86, 1998.
Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC,
Abrams JS, Boyce B, Broxmeyer H, and Manolagas SC. Increased osteoclast development after estrogen loss: mediation by
interleukin-6. Science 257: 88 –91, 1992.
Johnston B, Burns AR, Suematsu M, Issekutz TB, Woodman
RC, and Kubes P. Chronic inflammation upregulates chemokine
receptors and induces neutrophil migration to monocyte chemoattractant protein-1. J Clin Invest 103: 1269 –1276, 1999.
Jonasson L, Bondjers G, and Hansson GK. Lipoprotein lipase in
atherosclerosis: its presence in smooth muscle cells and absence
from macrophages. J Lipid Res 28: 437– 445, 1987.
Jong MC, Hendriks WL, van Vark LC, Dahlmans VE, Groener
JE, and Havekes LM. Oxidized VLDL induces less triglyceride
accumulation in J774 macrophages than native VLDL due to an
impaired extracellular lipolysis. Arterioscler Thromb Vasc Biol 20:
144 –151, 2000.
Jorgensen L, Haerem JW, and Moe N. Platelet thrombosis and
non-traumatic intimal injury in mouse aorta. Thromb Diath Haemorrh 29: 470 – 489, 1973.
Jovinge S, Ares MP, Kallin B, and Nilsson J. Human monocytes/macrophages release TNF-alpha in response to Ox-LDL. Arterioscler Thromb Vasc Biol 16: 1573–1579, 1996.
Juliano RL and Haskill S. Signal transduction from the extracellular matrix. J Cell Biol 120: 577–585, 1993.
Kameyoshi Y, Dorschner A, Mallet AI, Christophers E, and
Schroder JM. Cytokine RANTES released by thrombin-stimulated
platelets is a potent attractant for human eosinophils. J Exp Med
176: 587–592, 1992.
Kansas GS. Structure and function of L-selectin. APMIS 100: 287–
293, 1992.
Kaplan M and Aviram M. Oxidized low density lipoprotein:
atherogenic and proinflammatory characteristics during macrophage foam cell formation. An inhibitory role for nutritional antioxidants and serum paraoxonase. Clin Chem Lab Med 37: 777–787,
1999.
Kaplan M and Aviram M. Retention of oxidized LDL by extracellular matrix proteoglycans leads to its uptake by macrophages: an
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
218.
platelets triggers an inflammatory reaction of endothelial cells.
Nature 391: 591–594, 1998.
Hill AA, Coleman RA, Taylor GW, Moore KP, and Taylor IK.
Effect of the isoprostanes, 8-iso prostaglandin E2 and 8-iso prostaglandin F2 alpha on the rabbit lung in vivo. Prostaglandins 53:
69 – 82, 1997.
Hiltunen T, Luoma J, Nikkari T, and Yla-Herttuala S. Induction of 15-lipoxygenase mRNA and protein in early atherosclerotic
lesions. Circulation 92: 3297–3303, 1995.
Hirabayashi T, Kume K, Hirose K, Yokomizo T, Iino M, Itoh H,
and Shimizu T. Critical duration of intracellular Ca2⫹ response
required for continuous translocation and activation of cytosolic
phospholipase A2. J Biol Chem 274: 5163–5169, 1999.
Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang
B, Sato K, Shimizu M, Maini R, Feldmann M, and Kishimoto T.
Excessive production of interleukin 6/B cell stimulatory factor-2 in
rheumatoid arthritis. Eur J Immunol 18: 1797–1801, 1988.
Hjelms E, Nordestgaard BG, Stender S, and Kjeldsen K. A
surgical model to study in vivo efflux of cholesterol from porcine
aorta. Evidence for cholesteryl ester transfer through the aortic
wall. Atherosclerosis 77: 239 –249, 1989.
Hofnagel O, Luechtenborg B, Plenz G, and Robenek H. Expression of the novel scavenger receptor SR-PSOX in cultured
aortic smooth muscle cells and umbilical endothelial cells. Arterioscler Thromb Vasc Biol 22: 710 –711, 2002.
Honda HM, Leitinger N, Frankel M, Goldhaber JI, Natarajan
R, Nadler JL, Weiss JN, and Berliner JA. Induction of monocyte
binding to endothelial cells by MM-LDL: role of lipoxygenase metabolites. Arterioscler Thromb Vasc Biol 19: 680 – 686, 1999.
Hoover RL, Karnovsky MJ, Austen KF, Corey EJ, and Lewis
RA. Leukotriene B4 action on endothelium mediates augmented
neutrophil/endothelial adhesion. Proc Natl Acad Sci USA 81: 2191–
2193, 1984.
Huang Y, Jaffa A, Koskinen S, Takei A, and Lopes-Virella MF.
Oxidized LDL-containing immune complexes induce Fc gamma
receptor I-mediated mitogen-activated protein kinase activation in
THP-1 macrophages. Arterioscler Thromb Vasc Biol 19: 1600 –1607,
1999.
Huang Y, Mironova M, and Lopes-Virella MF. Oxidized LDL
stimulates matrix metalloproteinase-1 expression in human vascular endothelial cells. Arterioscler Thromb Vasc Biol 19: 2640 –2647,
1999.
Huang ZH, Bates EJ, Ferrante JV, Hii CS, Poulos A, Robinson
BS, and Ferrante A. Inhibition of stimulus-induced endothelial
cell intercellular adhesion molecule-1, E-selectin, and vascular cellular adhesion molecule-1 expression by arachidonic acid and its
hydroxy and hydroperoxy derivatives. Circ Res 80: 149 –158, 1997.
Hubacek JA, Rothe G, Pit’ha J, Skodova Z, Stanek V, Poledne
R, and Schmitz G. C (⫺260)–3 T polymorphism in the promoter
of the CD14 monocyte receptor gene as a risk factor for myocardial
infarction. Circulation 99: 3218 –3220, 1999.
Hubbard AK and Rothlein R. Intercellular adhesion molecule-1
(ICAM-1) expression and cell signaling cascades. Free Radic Biol
Med 28: 1379 –1386, 2000.
Huber SA, Sakkinen P, Conze D, Hardin N, and Tracy R.
Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol 19: 2364 –2367, 1999.
Huo Y and Ley K. Adhesion molecules and atherogenesis. Acta
Physiol Scand 173: 35– 43, 2001.
Hurt-Camejo E, Andersen S, Standal R, Rosengren B, Sartipy
P, Stadberg E, and Johansen B. Localization of nonpancreatic
secretory phospholipase A2 in normal and atherosclerotic arteries.
Activity of the isolated enzyme on low-density lipoproteins. Arterioscler Thromb Vasc Biol 17: 300 –309, 1997.
Idriss HT and Naismith JH. TNF alpha and the TNF receptor
superfamily: structure-function relationship(s). Microsc Res Tech
50: 184 –195, 2000.
Iiyama K, Hajra L, Iiyama M, Li H, DiChiara M, Medoff BD,
and Cybulsky MI. Patterns of vascular cell adhesion molecule-1
and intercellular adhesion molecule-1 expression in rabbit and
mouse atherosclerotic lesions and at sites predisposed to lesion
formation. Circ Res 85: 199 –207, 1999.
Inaba T, Shimano H, Gotoda T, Harada K, Shimada M, Ohsuga
1103
1104
251.
252.
253.
254.
255.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.
267.
268.
269.
alternative approach to study lipoproteins cellular uptake. Arterioscler Thromb Vasc Biol 21: 386 –393, 2001.
Kaplanski G, Porat R, Aiura K, Erban JK, Gelfand JA, and
Dinarello CA. Activated platelets induce endothelial secretion of
interleukin-8 in vitro via an interleukin-1-mediated event. Blood 81:
2492–2495, 1993.
Kato M, Tokuyama K, Morikawa A, Kuroume T, and Barnes
PJ. Platelet-activating factor-induced enhancement of superoxide
anion generation in guinea-pigs. Eur J Pharmacol 232: 7–12, 1993.
Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K,
Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto A, and
Kishimoto T. Autocrine generation and requirement of BSF-2/IL-6
for human multiple myelomas. Nature 332: 83– 85, 1988.
Khoo JC, Miller E, McLoughlin P, and Steinberg D. Enhanced
macrophage uptake of low density lipoprotein after self-aggregation. Arteriosclerosis 8: 348 –358, 1988.
Khoo JC, Miller E, Pio F, Steinberg D, and Witztum JL.
Monoclonal antibodies against LDL further enhance macrophage
uptake of LDL aggregates. Arterioscler Thromb 12: 1258 –1266,
1992.
Kim JA, Territo MC, Wayner E, Carlos TM, Parhami F, Smith
CW, Haberland ME, Fogelman AM, and Berliner JA. Partial
characterization of leukocyte binding molecules on endothelial
cells induced by minimally oxidized LDL. Arterioscler Thromb 14:
427– 433, 1994.
King VL, Szilvassy SJ, and Daugherty A. Interleukin-4 deficiency decreases atherosclerotic lesion formation in a site-specific
manner in female LDL receptor ⫺/⫺ mice. Arterioscler Thromb
Vasc Biol 22: 456 – 461, 2002.
Kirk EA, Dinauer MC, Rosen H, Chait A, Heinecke JW, and
LeBoeuf RC. Impaired superoxide production due to a deficiency
in phagocyte NADPH oxidase fails to inhibit atherosclerosis in
mice. Arterioscler Thromb Vasc Biol 20: 1529 –1535, 2000.
Kirsch CM, Sigal E, Djokic TD, Graf PD, and Nadel JA. An in
vivo chemotaxis assay in the dog trachea: evidence for chemotactic
activity of 8,15-diHETE. J Appl Physiol 64: 1792–1795, 1988.
Kishimoto T, Akira S, Narazaki M, and Taga T. Interleukin-6
family of cytokines and gp130. Blood 86: 1243–1254, 1995.
Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U,
Mangelsdorf DJ, Umesono K, and Evans RM. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91: 7355–7359,
1994.
Kliewer SA, Umesono K, Noonan DJ, Heyman RA, and Evans
RM. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their
receptors. Nature 358: 771–774, 1992.
Kliewer SA and Willson TM. The nuclear receptor PPARgamma:
bigger than fat. Curr Opin Genet Dev 8: 576 –581, 1998.
Klinger MH, Wilhelm D, Bubel S, Sticherling M, Schroder JM,
and Kuhnel W. Immunocytochemical localization of the chemokines RANTES and MIP-1 alpha within human platelets and their
release during storage. Int Arch Allergy Immunol 107: 541–546,
1995.
Klouche M, May AE, Hemmes M, Messner M, Kanse SM,
Preissner KT, and Bhakdi S. Enzymatically modified, nonoxidized LDL induces selective adhesion and transmigration of monocytes and T-lymphocytes through human endothelial cell monolayers. Arterioscler Thromb Vasc Biol 19: 784 –793, 1999.
Knowles JW and Maeda N. Genetic modifiers of atherosclerosis
in mice. Arterioscler Thromb Vasc Biol 20: 2336 –2345, 2000.
Koenig W, Rothenbacher D, Hoffmeister A, Miller M, Bode G,
Adler G, Hombach V, Marz W, Pepys MB, and Brenner H.
Infection with Helicobacter pylori is not a major independent risk
factor for stable coronary heart disease: lack of a role of cytotoxinassociated protein A-positive strains and absence of a systemic
inflammatory response. Circulation 100: 2326 –2331, 1999.
Koike J, Nagata K, Kudo S, Tsuji T, and Irimura T. Densitydependent induction of TNF-alpha release from human monocytes
by immobilized P-selectin. FEBS Lett 477: 84 – 88, 2000.
Kol A, Bourcier T, Lichtman AH, and Libby P. Chlamydial and
human heat shock protein 60s activate human vascular endothePhysiol Rev • VOL
270.
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
288.
lium, smooth muscle cells, and macrophages. J Clin Invest 103:
571–577, 1999.
Kol A, Lichtman AH, Finberg RW, Libby P, and Kurt-Jones
EA. Cutting edge: heat shock protein (HSP) 60 activates the innate
immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J Immunol 164: 13–17, 2000.
Kol A, Sukhova GK, Lichtman AH, and Libby P. Chlamydial
heat shock protein 60 localizes in human atheroma and regulates
macrophage tumor necrosis factor-alpha and matrix metalloproteinase expression. Circulation 98: 300 –307, 1998.
Kowala MC, Recce R, Beyer S, Gu C, and Valentine M. Characterization of atherosclerosis in LDL receptor knockout mice:
macrophage accumulation correlates with rapid and sustained expression of aortic MCP-1/JE. Atherosclerosis 149: 323–330, 2000.
Krakauer T. Human interleukin 1. Crit Rev Immunol 6: 213–244,
1986.
Kramer RM, Jakubowski JA, and Deykin D. Hydrolysis of 1-alkyl-2-arachidonoyl-sn-glycero-3-phosphocholine, a common precursor of platelet-activating factor and eicosanoids, by human
platelet phospholipase A2. Biochim Biophys Acta 959: 269 –279,
1988.
Kreisle RA and Parker CW. Specific binding of leukotriene B4 to
a receptor on human polymorphonuclear leukocytes. J Exp Med
157: 628 – 641, 1983.
Krieg P, Kinzig A, Heidt M, Marks F, and Furstenberger G.
cDNA cloning of a 8-lipoxygenase and a novel epidermis-type lipoxygenase from phorbol ester-treated mouse skin. Biochim Biophys Acta 1391: 7–12, 1998.
Kubes P, Ibbotson G, Russell J, Wallace JL, and Granger DN.
Role of platelet-activating factor in ischemia/reperfusion-induced
leukocyte adherence. Am J Physiol Gastrointest Liver Physiol 259:
G300 –G305, 1990.
Kume N and Kita T. Roles of lectin-like oxidized LDL receptor-1
and its soluble forms in atherogenesis. Curr Opin Lipidol 12:
419 – 423, 2001.
Kuna P, Reddigari SR, Schall TJ, Rucinski D, Viksman MY,
and Kaplan AP. RANTES, a monocyte and T lymphocyte chemotactic cytokine releases histamine from human basophils. J Immunol 149: 636 – 642, 1992.
Langer C, Huang Y, Cullen P, Wiesenhutter B, Mahley RW,
Assmann G, and von Eckardstein A. Endogenous apolipoprotein
E modulates cholesterol efflux and cholesteryl ester hydrolysis
mediated by high-density lipoprotein-3 and lipid-free apolipoproteins in mouse peritoneal macrophages. J Mol Med 78: 217–227,
2000.
Le JM, Weinstein D, Gubler U, and Vilcek J. Induction of
membrane-associated interleukin 1 by tumor necrosis factor in
human fibroblasts. J Immunol 138: 2137–2142, 1987.
Lee E, Grodzinsky AJ, Libby P, Clinton SK, Lark MW, and Lee
RT. Human vascular smooth muscle cell-monocyte interactions
and metalloproteinase secretion in culture. Arterioscler Thromb
Vasc Biol 15: 2284 –2289, 1995.
Lee TH, Hoover RL, Williams JD, Sperling RI, Ravalese JD,
Spur BW, Robinson DR, Corey EJ, Lewis RA, and Austen KF.
Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene
generation and neutrophil function. N Engl J Med 312: 1217–1224,
1985.
Lee TS, Yen HC, Pan CC, and Chau LY. The role of interleukin
12 in the development of atherosclerosis in ApoE-deficient mice.
Arterioscler Thromb Vasc Biol 19: 734 –742, 1999.
Lee WH, Kim SH, Lee Y, Lee BB, Kwon B, Song H, Kwon BS,
and Park JE. Tumor necrosis factor receptor superfamily 14 is
involved in atherogenesis by inducing proinflammatory cytokines
and matrix metalloproteinases. Arterioscler Thromb Vasc Biol 21:
2004 –2010, 2001.
Lefer DJ and Granger DN. Monocyte rolling in early atherogenesis: vital role in lesion development. Circ Res 84: 1353–1355, 1999.
Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, and
Kliewer SA. Peroxisome proliferator-activated receptors alpha
and gamma are activated by indomethacin and other non-steroidal
anti-inflammatory drugs. J Biol Chem 272: 3406 –3410, 1997.
Lehr HA, Sagban TA, Ihling C, Zahringer U, Hungerer KD,
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
256.
BJARNE ØSTERUD AND EIRIK BJØRKLID
MONOCYTES IN ATHEROGENESIS
289.
290.
291.
292.
294.
295.
296.
297.
298.
299.
300.
301.
302.
303.
304.
305.
306.
307.
308.
309.
Physiol Rev • VOL
310.
311.
312.
313.
314.
315.
316.
317.
318.
319.
320.
321.
322.
323.
324.
325.
326.
327.
328.
329.
330.
Murakami M, Kishimoto T, and Shoyab M. Interleukin-6 signal
transducer gp130 mediates oncostatin M signaling. J Biol Chem
267: 16763–16766, 1992.
Lobb RR and Hemler ME. The pathophysiologic role of alpha 4
integrins in vivo. J Clin Invest 94: 1722–1728, 1994.
Locksley RM, Killeen N, and Lenardo MJ. The TNF and TNF
receptor superfamilies: integrating mammalian biology. Cell 104:
487–501, 2001.
Loppnow H, Werdan K, Reuter G, and Flad HD. The interleukin-1 and interleukin-1 converting enzyme families in the cardiovascular system. Eur Cytokine Network 9: 675– 680, 1998.
Loppnow H, Westphal E, Buchhorn R, Wessel A, and Werdan
K. Interleukin-1 and related proteins in cardiovascular disease in
adults and children. Shock 16 Suppl 1: 3–9, 2001.
Lund T and Østerud B. Fibrinogen increases lipopolysaccharideinduced tumor necrosis factor-alpha and interleukin-8 release, and
enhances tissue factor activity in monocytes in a modified whole
blood system. Blood Coagul Fibrinolysis 12: 667– 675, 2001.
Mach F. The role of chemokines in atherosclerosis. Curr Atheroscler Rep 3: 243–251, 2001.
Mach F, Schonbeck U, Sukhova GK, Atkinson E, and Libby P.
Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 394: 200 –203, 1998.
Mach F, Schonbeck U, Sukhova GK, Bourcier T, Bonnefoy JY,
Pober JS, and Libby P. Functional CD40 ligand is expressed on
human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci USA 94: 1931–1936, 1997.
Maddox JF and Serhan CN. Lipoxin A4 and B4 are potent stimuli
for human monocyte migration and adhesion: selective inactivation
by dehydrogenation and reduction. J Exp Med 183: 137–146, 1996.
Madej A, Okopien B, Kowalski J, Zielinski M, Wysocki J,
Szygula B, Kalina Z, and Herman ZS. Effects of fenofibrate on
plasma cytokine concentrations in patients with atherosclerosis
and hyperlipoproteinemia IIb. Int J Clin Pharmacol Ther 36: 345–
349, 1998.
Malinauskas RA, Herrmann RA, and Truskey GA. The distribution of intimal white blood cells in the normal rabbit aorta.
Atherosclerosis 115: 147–163, 1995.
Mallat Z, Besnard S, Duriez M, Deleuze V, Emmanuel F, Bureau MF, Soubrier F, Esposito B, Duez H, Fievet C, Staels B,
Duverger N, Scherman D, and Tedgui A. Protective role of
interleukin-10 in atherosclerosis. Circ Res 85: 17–24, 1999.
Mallat Z, Heymes C, Ohan J, Faggin E, Leseche G, and Tedgui
A. Expression of interleukin-10 in advanced human atherosclerotic
plaques: relation to inducible nitric oxide synthase expression and
cell death. Arterioscler Thromb Vasc Biol 19: 611– 616, 1999.
Mallat Z, Nakamura T, Ohan J, Leseche G, Tedgui A, Maclouf
J, and Murphy RC. The relationship of hydroxyeicosatetraenoic
acids and F2-isoprostanes to plaque instability in human carotid
atherosclerosis. J Clin Invest 103: 421– 427, 1999.
Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G,
Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, and
Evans RM. The nuclear receptor superfamily: the second decade.
Cell 83: 835– 839, 1995.
Manka D, Collins R, Ley K, Beaudet A, and Sarembock I.
Absence of P-selectin, but not ICAM-1, attenuates neointimal
growth after injury in apolipoprotein-E-deficient mice. Circulation
103: 1000 –1005, 2001.
Mann KG. Biochemistry and physiology of blood coagulation.
Thromb Haemost 82: 165–174, 1999.
Mantovani A. The interplay between primary and secondary cytokines. Cytokines involved in the regulation of monocyte recruitment. Drugs 54: 15–23, 1997.
Marshall LA, Bolognese B, and Roshak A. Respective roles of
the 14 kDa and 85 kDa phospholipase A2 enzymes in human monocyte eicosanoid formation. Adv Exp Med Biol 469: 215–219, 1999.
Marshall LA, Bolognese B, Winkler JD, and Roshak A. Depletion of human monocyte 85-kDa phospholipase A2 does not alter
leukotriene formation. J Biol Chem 272: 759 –765, 1997.
Martens JS, Lougheed M, Gomez-Munoz A, and Steinbrecher
UP. A modification of apolipoprotein B accounts for most of the
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
293.
Blumrich M, Reifenberg K, and Bhakdi S. Immunopathogenesis
of atherosclerosis: endotoxin accelerates atherosclerosis in rabbits
on hypercholesterolemic diet. Circulation 104: 914 –920, 2001.
Leitinger N, Blazek I, and Sinzinger H. The influence of isoprostanes on ADP-induced platelet aggregation and cyclic AMPgeneration in human platelets. Thromb Res 86: 337–342, 1997.
Leitinger N, Watson AD, Faull KF, Fogelman AM, and Berliner JA. Monocyte binding to endothelial cells induced by oxidized phospholipids present in minimally oxidized low density
lipoprotein is inhibited by a platelet activating factor receptor
antagonist. Adv Exp Med Biol 433: 379 –382, 1997.
Leitinger N, Watson AD, Hama SY, Ivandic B, Qiao JH, Huber
J, Faull KF, Grass DS, Navab M, Fogelman AM, de Beer FC,
Lusis AJ, and Berliner JA. Role of group II secretory phospholipase A2 in atherosclerosis. 2. Potential involvement of biologically
active oxidized phospholipids. Arterioscler Thromb Vasc Biol 19:
1291–1298, 1999.
Lemberger T, Desvergne B, and Wahli W. Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in
lipid physiology. Annu Rev Cell Dev Biol 12: 335–363, 1996.
Leonard EJ and Yoshimura T. Human monocyte chemoattractant protein-1 (MCP-1). Immunol Today 11: 97–101, 1990.
Lessner SM, Prado HL, Waller EK, and Galis ZS. Atherosclerotic lesions grow through recruitment and proliferation of circulating monocytes in a murine model. Am J Pathol 160: 2145–2155,
2002.
Leus FR, Wittekoek ME, Prins J, Kastelein JJ, and Voorbij
HA. Paraoxonase gene polymorphisms are associated with carotid
arterial wall thickness in subjects with familial hypercholesterolemia. Atherosclerosis 149: 371–377, 2000.
Levy BD, Romano M, Chapman HA, Reilly JJ, Drazen J, and
Serhan CN. Human alveolar macrophages have 15-lipoxygenase
and generate 15 (S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic
acid and lipoxins. J Clin Invest 92: 1572–1579, 1993.
Ley K. Molecular mechanisms of leukocyte recruitment in the
inflammatory process. Cardiovasc Res 32: 733–742, 1996.
Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, and
Glass CK. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 106: 523–531, 2000.
Li Q and Cathcart MK. Selective inhibition of cytosolic phospholipase A2 in activated human monocytes. Regulation of superoxide
anion production and low density lipoprotein oxidation. J Biol
Chem 272: 2404 –2411, 1997.
Li W, Yuan XM, and Brunk UT. OxLDL-induced macrophage
cytotoxicity is mediated by lysosomal rupture and modified by
intralysosomal redox-active iron. Free Radic Res 29: 389 –398, 1998.
Liao F, Andalibi A, Lusis AJ, and Fogelman AM. Genetic control of the inflammatory response induced by oxidized lipids. Am J
Cardiol 75: 65B– 66B, 1995.
Liao F, Andalibi A, Qiao JH, Allayee H, Fogelman AM, and
Lusis AJ. Genetic evidence for a common pathway mediating
oxidative stress, inflammatory gene induction, and aortic fatty
streak formation in mice. J Clin Invest 94: 877– 884, 1994.
Liao F, Huynh HK, Eiroa A, Greene T, Polizzi E, and Muller
WA. Migration of monocytes across endothelium and passage
through extracellular matrix involve separate molecular domains
of PECAM-1. J Exp Med 182: 1337–1343, 1995.
Libby P and Galis ZS. Cytokines regulate genes involved in
atherogenesis. Ann NY Acad Sci 748: 158 –170, 1995.
Libby P, Sukhova G, Lee RT, and Galis ZS. Cytokines regulate
vascular functions related to stability of the atherosclerotic plaque.
J Cardiovasc Pharmacol 25: S9 –S12, 1995.
Lin LL, Wartmann M, Lin AY, Knopf JL, Seth A, and Davis RJ.
cPLA2 is phosphorylated and activated by MAP kinase. Cell 72:
269 –278, 1993.
Lindmark E, Tenno T, and Siegbahn A. Role of platelet Pselectin and CD40 ligand in the induction of monocytic tissue
factor expression. Arterioscler Thromb Vasc Biol 20: 2322–2328,
2000.
Lipsky PE. Role of cyclooxygenase-1 and -2 in health and disease.
Am J Orthop 28: 8 –12, 1999.
Liu J, Modrell B, Aruffo A, Marken JS, Taga T, Yasukawa K,
1105
1106
331.
332.
333.
334.
336.
337.
338.
339.
340.
341.
342.
343.
344.
345.
346.
347.
348.
349.
induction of macrophage growth by oxidized low density lipoprotein. J Biol Chem 274: 10903–10910, 1999.
Marx N, Schonbeck U, Lazar MA, Libby P, and Plutzky J.
Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth
muscle cells. Circ Res 83: 1097–1103, 1998.
Marx N, Sukhova G, Murphy C, Libby P, and Plutzky J. Macrophages in human atheroma contain PPARgamma: differentiationdependent peroxisomal proliferator-activated receptor gamma
(PPARgamma) expression and reduction of MMP-9 activity
through PPARgamma activation in mononuclear phagocytes in
vitro. Am J Pathol 153: 17–23, 1998.
Matsumura T, Sakai M, Matsuda K, Furukawa N, Kaneko K,
and Shichiri M. Cis-acting DNA elements of mouse granulocyte/
macrophage colony-stimulating factor gene responsive to oxidized
low density lipoprotein. J Biol Chem 274: 37665–37672, 1999.
Mayr M, Kiechl S, Willeit J, Wick G, and Xu Q. Infections,
immunity, and atherosclerosis: associations of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus
with immune reactions to heat-shock protein 60 and carotid or
femoral atherosclerosis. Circulation 102: 833– 839, 2000.
McEver RP. Selectins: novel receptors that mediate leukocyte
adhesion during inflammation. Thromb Haemost 65: 223–228, 1991.
McGill HC Jr, McMahan CA, Herderick EE, Malcom GT, Tracy
RE, and Strong JP. Origin of atherosclerosis in childhood and
adolescence. Am J Clin Nutr 72: 1307S–1315S, 2000.
McIntyre TM, Zimmerman GA, and Prescott SM. Leukotrienes
C4 and D4 stimulate human endothelial cells to synthesize plateletactivating factor and bind neutrophils. Proc Natl Acad Sci USA 83:
2204 –2208, 1986.
McNally AK, Chisolm GMD, Morel DW, and Cathcart MK.
Activated human monocytes oxidize low-density lipoprotein by a
lipoxygenase-dependent pathway. J Immunol 145: 254 –259, 1990.
Meade TW, Cooper JA, Stirling Y, Howarth DJ, Ruddock V,
and Miller GJ. Factor VIII, ABO blood group and the incidence of
ischaemic heart disease. Br J Haematol 88: 601– 607, 1994.
Mehrabian M, Allayee H, Wong J, Shih W, Wang XP, Shaposhnik Z, Funk CD, and Lusis AJ. Identification of 5-lipoxygenase as
a major gene contributing to atherosclerosis susceptibility in mice.
Circ Res 91: 120 –126, 2002.
Menschikowski M, Kasper M, Lattke P, Schiering A, Schiefer
S, Stockinger H, and Jaross W. Secretory group II phospholipase
A2 in human atherosclerotic plaques. Atherosclerosis 118: 173–181,
1995.
Methia N, Andre P, Denis C, Economopoulos M, Subbarao S,
and Wagner DD. Delayed fatty streak formation in von Willebrand
factor-deficient mice (Abstract). Circulation 94 Suppl 1: 450a,
1999.
Methia N, Andre P, Denis CV, Economopoulos M, and Wagner
DD. Localized reduction of atherosclerosis in von Willebrand factor-deficient mice. Blood 98: 1424 –1428, 2001.
Miles SA, Rezai AR, Salazar-Gonzalez JF, Vander Meyden M,
Stevens RH, Logan DM, Mitsuyasu RT, Taga T, Hirano T,
Kishimoto T, and Martinez-Mozar D. AIDS Kaposi sarcomaderived cells produce and respond to interleukin 6. Proc Natl Acad
Sci USA 87: 4068 – 4072, 1990.
Moore KL, Stults NL, Diaz S, Smith DF, Cummings RD, Varki
A, and McEver RP. Identification of a specific glycoprotein ligand
for P-selectin (CD62) on myeloid cells. J Cell Biol 118: 445– 456,
1992.
Morel DW, Hessler JR, and Chisolm GM. Low density lipoprotein cytotoxicity induced by free radical peroxidation of lipid. J
Lipid Res 24: 1070 –1076, 1983.
Morita I, Schindler M, Regier MK, Otto JC, Hori T, DeWitt
DL, and Smith WL. Different intracellular locations for prostaglandin endoperoxide H synthase-1 and -2. J Biol Chem 270: 10902–
10908, 1995.
Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, and
Roberts LJ II. A series of prostaglandin F2-like compounds are
produced in vivo in humans by a non-cyclooxygenase, free radicalcatalyzed mechanism. Proc Natl Acad Sci USA 87: 9383–9387, 1990.
Mortensen RF, Osmand AP, Lint TF, and Gewurz H. Interaction of C-reactive protein with lymphocytes and monocytes: comPhysiol Rev • VOL
350.
351.
352.
353.
354.
355.
356.
357.
358.
359.
360.
361.
362.
363.
364.
365.
366.
367.
plement-dependent adherence and phagocytosis. J Immunol 117:
774 –781, 1976.
Mueller HW, Purdon AD, Smith JB, and Wykle RL. 1-O-alkyllinked phosphoglycerides of human platelets: distribution of arachidonate and other acyl residues in the ether-linked and diacyl
species. Lipids 18: 814 – 819, 1983.
Muller E, Dagenais P, Alami N, and Rola-Pleszczynski M.
Identification and functional characterization of platelet-activating
factor receptors in human leukocyte populations using polyclonal
anti-peptide antibody. Proc Natl Acad Sci USA 90: 5818 –5822, 1993.
Muller WA. The role of PECAM-1 (CD31) in leukocyte emigration:
studies in vitro and in vivo. J Leukoc Biol 57: 523–528, 1995.
Munder M, Mallo M, Eichmann K, and Modolell M. Murine
macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: a novel pathway of autocrine macrophage activation. J Exp Med 187: 2103–2108, 1998.
Murakami M, Kudo I, and Inoue K. Eicosanoid generation from
antigen-primed mast cells by extracellular mammalian 14-kDa
group II phospholipase A2. FEBS Lett 294: 247–251, 1991.
Murakami M, Kudo I, and Inoue K. Secretory phospholipases A2.
J Lipid Mediat Cell Signal 12: 119 –130, 1995.
Murohara T, Scalia R, and Lefer AM. Lysophosphatidylcholine
promotes P-selectin expression in platelets and endothelial cells.
Possible involvement of protein kinase C activation and its inhibition by nitric oxide donors. Circ Res 78: 780 –789, 1996.
Musso T, Deaglio S, Franco L, Calosso L, Badolato R, Garbarino G, Dianzani U, and Malavasi F. CD38 expression and
functional activities are up-regulated by IFN-gamma on human
monocytes and monocytic cell lines. J Leukoc Biol 69: 605– 612,
2001.
Nagano H, Mitchell RN, Taylor MK, Hasegawa S, Tilney NL,
and Libby P. Interferon-gamma deficiency prevents coronary arteriosclerosis but not myocardial rejection in transplanted mouse
hearts. J Clin Invest 100: 550 –557, 1997.
Nagase H and Woessner JF Jr. Matrix metalloproteinases. J Biol
Chem 274: 21491–21494, 1999.
Nagy L, Tontonoz P, Alvarez JG, Chen H, and Evans RM.
Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 93: 229 –240, 1998.
Nakano T, Raines EW, Abraham JA, Klagsbrun M, and Ross R.
Lysophosphatidylcholine upregulates the level of heparin-binding
epidermal growth factor-like growth factor mRNA in human monocytes. Proc Natl Acad Sci USA 91: 1069 –1073, 1994.
Nakashima Y, Raines EW, Plump AS, Breslow JL, and Ross R.
Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites
on the endothelium in the ApoE-deficient mouse. Arterioscler
Thromb Vasc Biol 18: 842– 851, 1998.
Nakata A, Nakagawa Y, Nishida M, Nozaki S, Miyagawa J,
Nakagawa T, Tamura R, Matsumoto K, Kameda-Takemura K,
Yamashita S, and Matsuzawa Y. CD36, a novel receptor for
oxidized low-density lipoproteins, is highly expressed on lipidladen macrophages in human atherosclerotic aorta. Arterioscler
Thromb Vasc Biol 19: 1333–1339, 1999.
Naldini A, Sower L, Bocci V, Meyers B, and Carney DH. Thrombin receptor expression and responsiveness of human monocytic
cells to thrombin is linked to interferon-induced cellular differentiation. J Cell Physiol 177: 76 – 84, 1998.
Nalefski EA, Wisner MA, Chen JZ, Sprang SR, Fukuda M,
Mikoshiba K, and Falke JJ. C2 domains from different Ca2⫹
signaling pathways display functional and mechanistic diversity.
Biochemistry 40: 3089 –3100, 2001.
Namiki M, Kawashima S, Yamashita T, Ozaki M, Hirase T,
Ishida T, Inoue N, Hirata K, Matsukawa A, Morishita R,
Kaneda Y, and Yokoyama M. Local overexpression of monocyte
chemoattractant protein-1 at vessel wall induces infiltration of
macrophages and formation of atherosclerotic lesion: synergism
with hypercholesterolemia. Arterioscler Thromb Vasc Biol 22: 115–
120, 2002.
Napoli C, D’Armiento FP, Mancini FP, Postiglione A, Witztum
JL, Palumbo G, and Palinski W. Fatty streak formation occurs in
human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
335.
BJARNE ØSTERUD AND EIRIK BJØRKLID
MONOCYTES IN ATHEROGENESIS
Physiol Rev • VOL
386. Østerud B, Lindahl U, and Seljelid R. Macrophages produce
blood coagulation factors. FEBS Lett 120: 41– 43, 1980.
387. Østerud B, Olsen JO, and Wilsgard L. Increased lipopolysaccharide-induced tissue factor activity and tumour necrosis factor production in monocytes after intake of aspirin: possible role of prostaglandin E2. Blood Coagul Fibrinolysis 3: 309 –313, 1992.
388. Ouellet S, Muller E, and Rola-Pleszczynski M. IFN-gamma
up-regulates platelet-activating factor receptor gene expression in
human monocytes. J Immunol 152: 5092–5099, 1994.
390. Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, and
Witztum JL. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific
epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb 14: 605– 616, 1994.
391. Palkama T. Induction of interleukin-1 production by ligands binding to the scavenger receptor in human monocytes and the THP-1
cell line. Immunology 74: 432– 438, 1991.
392. Palkama T, Matikainen S, and Hurme M. Tyrosine kinase activity is involved in the protein kinase C induced expression of
interleukin-1 beta gene in monocytic cells. FEBS Lett 319: 100 –104,
1993.
393. Pan ZK. Anaphylatoxins C5a and C3a induce nuclear factor kappaB activation in human peripheral blood monocytes. Biochim
Biophys Acta 1443: 90 –98, 1998.
394. Parhami F, Fang ZT, Fogelman AM, Andalibi A, Territo MC,
and Berliner JA. Minimally modified low density lipoproteininduced inflammatory responses in endothelial cells are mediated
by cyclic adenosine monophosphate. J Clin Invest 92: 471– 478,
1993.
395. Park SK, Yang WS, Lee SK, Ahn H, Park JS, Hwang O, and Lee
JD. TGF-beta (1) down-regulates inflammatory cytokine-induced
VCAM-1 expression in cultured human glomerular endothelial
cells. Nephrol Dial Transplant 15: 596 – 604, 2000.
396. Parthasarathy S, Wieland E, and Steinberg D. A role for endothelial cell lipoxygenase in the oxidative modification of low density lipoprotein. Proc Natl Acad Sci USA 86: 1046 –1050, 1989.
397. Patel SS, Thiagarajan R, Willerson JT, and Yeh ET. Inhibition
of alpha4 integrin and ICAM-1 markedly attenuate macrophage
homing to atherosclerotic plaques in ApoE-deficient mice. Circulation 97: 75– 81, 1998.
398. Pawlowski NA, Abraham E, Hamill A, and Scott WA. The
cyclooxygenase and lipoxygenase activities of platelet-depleted
human monocytes. J Allergy Clin Immunol 74: 324 –330, 1984.
399. Pawlowski NA, Kaplan G, Hamill AL, Cohn ZA, and Scott WA.
Arachidonic acid metabolism by human monocytes. Studies with
platelet-depleted cultures. J Exp Med 158: 393– 412, 1983.
400. Penn MS, Saidel GM, and Chisolm GM. Relative significance of
endothelium and internal elastic lamina in regulating the entry of
macromolecules into arteries in vivo. Circ Res 74: 74 – 82, 1994.
401. Pepinsky B, Hession C, Chen LL, Moy P, Burkly L,
Jakubowski A, Chow EP, Benjamin C, Chi-Rosso G, Luhowskyj S, and Lobb R. Structure/function studies on vascular
cell adhesion molecule-1. J Biol Chem 267: 17820 –17826, 1992.
402. Peplow PV. Regulation of platelet-activating factor (PAF) activity
in human diseases by phospholipase A2 inhibitors, PAF acetylhydrolases, PAF receptor antagonists and free radical scavengers.
Prostaglandins Leukotrienes Essent Fatty Acids 61: 65– 82, 1999.
403. Pernerstorfer T, Stohlawetz P, Hollenstein U, Dzirlo L,
Eichler HG, Kapiotis S, Jilma B, and Speiser W. Endotoxininduced activation of the coagulation cascade in humans: effect of
acetylsalicylic acid and acetaminophen. Arterioscler Thromb Vasc
Biol 19: 2517–2523, 1999.
404. Pernow J and Wang QD. Endothelin in myocardial ischaemia and
reperfusion. Cardiovasc Res 33: 518 –526, 1997.
405. Peters-Golden M. Cell biology of the 5-lipoxygenase pathway.
Am J Respir Crit Care Med 157: S227–S248, 1998.
406. Peters-Golden M, Song K, Marshall T, and Brock T. Translocation of cytosolic phospholipase A2 to the nuclear envelope elicits
topographically localized phospholipid hydrolysis. Biochem J 318:
797– 803, 1996.
407. Petersen F, Bock L, Flad HD, and Brandt E. Platelet factor
4-induced neutrophil-endothelial cell interaction: involvement of
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 100: 2680 –2690, 1997.
368. Narumiya S, Sugimoto Y, and Ushikubi F. Prostanoid receptors:
structures, properties, and functions. Physiol Rev 79: 1193–1226,
1999.
369. Nauck M, Roth M, Tamm M, Eickelberg O, Wieland H, Stulz P,
and Perruchoud AP. Induction of vascular endothelial growth
factor by platelet-activating factor and platelet-derived growth factor is downregulated by corticosteroids. Am J Respir Cell Mol Biol
16: 398 – 406, 1997.
370. Navab M, Berliner JA, Watson AD, Hama SY, Territo MC,
Lusis AJ, Shih DM, Van Lenten BJ, Frank JS, Demer LL,
Edwards PA, and Fogelman AM. The Yin and Yang of oxidation
in the development of the fatty streak. A review based on the 1994
George Lyman Duff Memorial Lecture. Arterioscler Thromb Vasc
Biol 16: 831– 842, 1996.
371. Navab M, Hama SY, Anantharamaiah GM, Hassan K, Hough
GP, Watson AD, Reddy ST, Sevanian A, Fonarow GC, and
Fogelman AM. Normal high density lipoprotein inhibits three
steps in the formation of mildly oxidized low density lipoprotein.
Steps 2 and 3. J Lipid Res 41: 1495–1508, 2000.
372. Nawroth PP, Bank I, Handley D, Cassimeris J, Chess L, and
Stern D. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med 163:
1363–1375, 1986.
373. Nelken NA, Coughlin SR, Gordon D, and Wilcox JN. Monocyte
chemoattractant protein-1 in human atheromatous plaques. J Clin
Invest 88: 1121–1127, 1991.
374. Newman PJ. The biology of PECAM-1. J Clin Invest 99: 3– 8, 1997.
375. Nielsen LB. Transfer of low density lipoprotein into the arterial
wall and risk of atherosclerosis. Atherosclerosis 123: 1–15, 1996.
376. Nithipatikom K, DiCamelli RF, Kohler S, Gumina RJ, Falck
JR, Campbell WB, and Gross GJ. Determination of cytochrome
P450 metabolites of arachidonic acid in coronary venous plasma
during ischemia and reperfusion in dogs. Anal Biochem 292: 115–
124, 2001.
376a.O’Connor D, Mihelic E, and Coleman M. Sterochemical course
of the auto-oxidative cyclization of lipid hydroperoxides to prostaglandin like bicyclo peroxides. J Am Chem Soc 106: 3577–3584,
1984.
377. O’Neill GP and Ford-Hutchinson AW. Expression of mRNA for
cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS
Lett 330: 156 –160, 1993.
378. Osnes LT, Foss KB, Joo GB, Okkenhaug C, Westvik AB,
Ovstebo R, and Kierulf P. Acetylsalicylic acid and sodium salicylate inhibit LPS-induced NF-kappa B/c-Rel nuclear translocation,
and synthesis of tissue factor (TF) and tumor necrosis factor alpha
(TNF-alpha) in human monocytes. Thromb Haemost 76: 970 –976,
1996.
379. Osnes LT, Haug KB, Joo GB, Westvik AB, Ovstebo R, and
Kierulf P. Aspirin potentiates LPS-induced fibrin formation (FPA)
and TNF-alpha-synthesis in whole blood. Thromb Haemost 83:
868 – 873, 2000.
380. Ost M, Uhl E, Carlsson M, Gidlof A, Soderkvist P, and Sirsjo
A. Expression of mRNA for phospholipase A2, cyclooxygenases,
and lipoxygenases in cultured human umbilical vascular endothelial and smooth muscle cells and in biopsies from umbilical arteries
and veins. J Vasc Res 35: 150 –155, 1998.
381. Østerud B. Platelet activating factor enhancement of lipopolysaccharide-induced tissue factor activity in monocytes: requirement of
platelets and granulocytes. J Leukoc Biol 51: 462– 465, 1992.
382. Østerud B. The high responder phenomenon: enhancement of LPS
induced tissue factor activity in monocytes by platelets and granulocytes. Platelets 6: 119 –125, 1995.
383. Østerud B. Tissue factor expression in monocytes: in vitro compared to ex vivo. Thromb Haemost 84: 521–522, 2000.
384. Østerud B, Bogwald J, Lindahl U, and Seljelid R. Production of
blood coagulation factor V and tissue thromboplastin by macrophages in vitro. FEBS Lett 127: 154 –160, 1981.
385. Østerud B, Elvevoll EO, Brox J, and Olsen JO. Cellular activation responses in blood in relation to lipid pattern: healthy men and
women in families with myocardial infarction or cancer. Blood
Coagul Fibrinolysis 13: 399 – 405, 2002.
1107
1108
408.
409.
410.
411.
413.
414.
415.
416.
417.
418.
419.
420.
421.
422.
423.
424.
425.
mechanisms and functional consequences different from those
elicited by interleukin-8. Blood 94: 4020 – 4028, 1999.
Petit L, Lesnik P, Dachet C, Moreau M, and Chapman MJ.
Tissue factor pathway inhibitor is expressed by human monocytederived macrophages: relationship to tissue factor induction by
cholesterol and oxidized LDL. Arterioscler Thromb Vasc Biol 19:
309 –315, 1999.
Pfister SL, Schmitz JM, Willerson JT, and Campbell WB.
Characterization of arachidonic acid metabolism in Watanabe heritable hyperlipidemic (WHHL) and New Zealand white (NZW) rabbit aortas. Prostaglandins 36: 515–532, 1988.
Philip R and Epstein LB. Tumour necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, gamma-interferon and interleukin-1. Nature 323: 86 – 89, 1986.
Pinderski Oslund LJ, Hedrick CC, Olvera T, Hagenbaugh A,
Territo M, Berliner JA, and Fyfe AI. Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Arterioscler Thromb Vasc
Biol 19: 2847–2853, 1999.
Podrez EA, Febbraio M, Sheibani N, Schmitt D, Silverstein
RL, Hajjar DP, Cohen PA, Frazier WA, Hoff HF, and Hazen SL.
Macrophage scavenger receptor CD36 is the major receptor for
LDL modified by monocyte-generated reactive nitrogen species.
J Clin Invest 105: 1095–1108, 2000.
Porreca E, Di Febbo C, Reale M, Barbacane R, Mezzetti A,
Cuccurullo F, and Conti P. Modulation of rat vascular smooth
muscle cell (VSMC) proliferation by cysteinyl leukotriene D4: a role
for mediation of interleukin 1. Atherosclerosis 113: 11–18, 1995.
Power CA, Meyer A, Nemeth K, Bacon KB, Hoogewerf AJ,
Proudfoot AE, and Wells TN. Molecular cloning and functional
expression of a novel CC chemokine receptor cDNA from a human
basophilic cell line. J Biol Chem 270: 19495–19500, 1995.
Pratico D, Iuliano L, Mauriello A, Spagnoli L, Lawson JA,
Rokach J, Maclouf J, Violi F, and FitzGerald GA. Localization
of distinct F2-isoprostanes in human atherosclerotic lesions. J Clin
Invest 100: 2028 –2034, 1997.
Prieto J, Eklund A, and Patarroyo M. Regulated expression of
integrins and other adhesion molecules during differentiation of
monocytes into macrophages. Cell Immunol 156: 191–211, 1994.
Pugin J, Ulevitch RJ, and Tobias PS. A critical role for monocytes and CD14 in endotoxin-induced endothelial cell activation. J
Exp Med 178: 2193–2200, 1993.
Qiu ZH, Gijon MA, de Carvalho MS, Spencer DM, and Leslie
CC. The role of calcium and phosphorylation of cytosolic phospholipase A2 in regulating arachidonic acid release in macrophages. J Biol Chem 273: 8203– 8211, 1998.
Quinn MT, Parthasarathy S, Fong LG, and Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci USA 84: 2995–2998, 1987.
Quinn MT, Parthasarathy S, and Steinberg D. Lysophosphatidylcholine: a chemotactic factor for human monocytes and its
potential role in atherogenesis. Proc Natl Acad Sci USA 85: 2805–
2809, 1988.
Rachmilewitz J and Tykocinski ML. Differential effects of chondroitin sulfates A and B on monocyte and B-cell activation: evidence for B-cell activation via a CD44-dependent pathway. Blood
92: 223–229, 1998.
Rajavashisth TB, Andalibi A, Territo MC, Berliner JA, Navab
M, Fogelman AM, and Lusis AJ. Induction of endothelial cell
expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature 344: 254 –257,
1990.
Rajavashisth TB, Yamada H, and Mishra NK. Transcriptional
activation of the macrophage-colony stimulating factor gene by
minimally modified LDL. Involvement of nuclear factor-kappa B.
Arterioscler Thromb Vasc Biol 15: 1591–1598, 1995.
Ramos CL, Huo Y, Jung U, Ghosh S, Manka DR, Sarembock IJ,
and Ley K. Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of
apolipoprotein E-deficient mice. Circ Res 84: 1237–1244, 1999.
Ramprasad MP, Terpstra V, Kondratenko N, Quehenberger O,
and Steinberg D. Cell surface expression of mouse macrosialin
and human CD68 and their role as macrophage receptors for
Physiol Rev • VOL
426.
427.
428.
429.
430.
431.
432.
433.
434.
435.
436.
437.
438.
439.
440.
441.
442.
443.
oxidized low density lipoprotein. Proc Natl Acad Sci USA 93:
14833–14838, 1996.
Rankin SM, Parthasarathy S, and Steinberg D. Evidence for a
dominant role of lipoxygenase (s) in the oxidation of LDL by mouse
peritoneal macrophages. J Lipid Res 32: 449 – 456, 1991.
Reale M, Barbacane RC, DiGioacchino M, Felaco M, Croce A,
Ferro FM, Lotti TM, and Conti P. Differential expression and
secretion of RANTES and MCP-1 in activated peripheral blood
mononuclear cell cultures of atopic subjects. Immunol Lett 76:
7–14, 2001.
Reape TJ and Groot PH. Chemokines and atherosclerosis. Atherosclerosis 147: 213–225, 1999.
Reape TJ, Rayner K, Manning CD, Gee AN, Barnette MS,
Burnand KG, and Groot PH. Expression and cellular localization
of the CC chemokines PARC and ELC in human atherosclerotic
plaques. Am J Pathol 154: 365–374, 1999.
Reardon CA, Blachowicz L, White T, Cabana V, Wang Y,
Lukens J, Bluestone J, and Getz GS. Effect of immune deficiency on lipoproteins and atherosclerosis in male apolipoprotein
E-deficient mice. Arterioscler Thromb Vasc Biol 21: 1011–1016,
2001.
Reckless J, Rubin EM, Verstuyft JB, Metcalfe JC, and
Grainger DJ. Monocyte chemoattractant protein-1 but not tumor
necrosis factor-alpha is correlated with monocyte infiltration in
mouse lipid lesions. Circulation 99: 2310 –2316, 1999.
Reddy ST, Winstead MV, Tischfield JA, and Herschman HR.
Analysis of the secretory phospholipase A2 that mediates prostaglandin production in mast cells. J Biol Chem 272: 13591–13596,
1997.
Rediske J, Morrissey MM, and Jarvis M. Human monocytes
respond to leukotriene B4 with a transient increase in cytosolic
calcium. Cell Immunol 147: 438 – 445, 1993.
Reid GK, Kargman S, Vickers PJ, Mancini JA, Leveille C,
Ethier D, Miller DK, Gillard JW, Dixon RA, and Evans JF.
Correlation between expression of 5-lipoxygenase-activating protein, 5-lipoxygenase, and cellular leukotriene synthesis. J Biol
Chem 265: 19818 –19823, 1990.
Ricote M, Huang J, Fajas L, Li A, Welch J, Najib J, Witztum
JL, Auwerx J, Palinski W, and Glass CK. Expression of the
peroxisome proliferator-activated receptor gamma (PPARgamma)
in human atherosclerosis and regulation in macrophages by colony
stimulating factors and oxidized low density lipoprotein. Proc Natl
Acad Sci USA 95: 7614 –7619, 1998.
Ricote M, Huang JT, Welch JS, and Glass CK. The peroxisome
proliferator-activated receptor (PPARgamma) as a regulator of
monocyte/macrophage function. J Leukoc Biol 66: 733–739, 1999.
Ridker PM and Haughie P. Prospective studies of C-reactive
protein as a risk factor for cardiovascular disease. J Invest Med 46:
391–395, 1998.
Ristimaki A, Garfinkel S, Wessendorf J, Maciag T, and Hla T.
Induction of cyclooxygenase-2 by interleukin-1 alpha. Evidence for
posttranscriptional regulation. J Biol Chem 269: 11769 –11775,
1994.
Roach MR, Fletcher J, and Cornhill JF. The effect of the duration of cholesterol feeding on the development of sudanophilic
lesions in the rabbit aorta. Atherosclerosis 25: 1–11, 1976.
Rola-Pleszczynski M, Thivierge M, Ouellet S, Dagenais P,
Parent JL, and Stankova J. Cytokines and eicosanoids regulate
PAF receptor gene expression. Adv Prostaglandin Thromboxane
Leukotriene Res 23: 287–292, 1995.
Romano M, Ricci V, Memoli A, Tuccillo C, Di Popolo A, Sommi
P, Acquaviva AM, Del Vecchio Blanco C, Bruni CB, and Zarrilli R. Helicobacter pylori up-regulates cyclooxygenase-2 mRNA
expression and prostaglandin E2 synthesis in MKN 28 gastric mucosal cells in vitro. J Biol Chem 273: 28560 –28563, 1998.
Rosen ED and Spiegelman BM. Peroxisome proliferator-activated receptor gamma ligands and atherosclerosis: ending the
heartache. J Clin Invest 106: 629 – 631, 2000.
Rosenfeld ME. Leukocyte recruitment into developing atherosclerotic lesions: the complex interaction between multiple molecules
keeps getting more complex. Arterioscler Thromb Vasc Biol 22:
361–363, 2002.
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
412.
BJARNE ØSTERUD AND EIRIK BJØRKLID
MONOCYTES IN ATHEROGENESIS
Physiol Rev • VOL
465.
466.
467.
468.
469.
470.
471.
472.
473.
474.
475.
476.
477.
478.
479.
480.
481.
482.
483.
structural study: implications in atherogenesis. Virchows Arch A
Pathol Anat Histopathol 405: 175–191, 1985.
Schwartz SM. The intima: a new soil. Circ Res 85: 877– 879, 1999.
Schwenke DC and St Clair RW. Influx, efflux, and accumulation
of LDL in normal arterial areas and atherosclerotic lesions of white
Carneau pigeons with naturally occurring and cholesterol-aggravated aortic atherosclerosis. Arterioscler Thromb 13: 1368 –1381,
1993.
Seeds MC and Bass DA. Regulation and metabolism of arachidonic acid. Clin Rev Allergy Immunol 17: 5–26, 1999.
Sempowski GD, Derdak S, and Phipps RP. Interleukin-4 and
interferon-gamma discordantly regulate collagen biosynthesis by
functionally distinct lung fibroblast subsets. J Cell Physiol 167:
290 –296, 1996.
Sendobry SM, Cornicelli JA, Welch K, Bocan T, Tait B,
Trivedi BK, Colbry N, Dyer RD, Feinmark SJ, and Daugherty
A. Attenuation of diet-induced atherosclerosis in rabbits with a
highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties. Br J Pharmacol 120: 1199 –1206, 1997.
Senis YA, Richardson M, Tinlin S, Maurice DH, and Giles AR.
Changes in the pattern of distribution of von Willebrand factor in
rat aortic endothelial cells following thrombin generation in vivo.
Br J Haematol 93: 195–203, 1996.
Serhan CN, Hamberg M, and Samuelsson B. Lipoxins: novel
series of biologically active compounds formed from arachidonic
acid in human leukocytes. Proc Natl Acad Sci USA 81: 5335–5339,
1984.
Setty BN, Berger M, and Stuart MJ. 13-Hydroxyoctadecadienoic
acid (13-HODE) stimulates prostacyclin production by endothelial
cells. Biochem Biophys Res Commun 146: 502–509, 1987.
Shak S, Perez HD, and Goldstein IM. A novel dioxygenation
product of arachidonic acid possesses potent chemotactic activity
for human polymorphonuclear leukocytes. J Biol Chem 258:
14948 –14953, 1983.
Shapiro SD, Campbell EJ, Senior RM, and Welgus HG. Proteinases secreted by human mononuclear phagocytes. J Rheumatol
Suppl 27: 95–98, 1991.
Shattock RJ, Rizzardi GP, Hayes P, and Griffin GE. Engagement of adhesion molecules (CD18, CD11a, CD45, CD44, and
CD58) enhances human immunodeficiency virus type 1 replication
in monocytic cells through a tumor necrosis factor-modulated
pathway. J Infect Dis 174: 54 – 62, 1996.
Shen J, Herderick E, Cornhill JF, Zsigmond E, Kim HS, Kuhn
H, Guevara NV, and Chan L. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development.
J Clin Invest 98: 2201–2208, 1996.
Shen RF and Tai HH. Thromboxanes: synthase and receptors.
J Biomed Sci 5: 153–172, 1998.
Shi W, Haberland ME, Jien ML, Shih DM, and Lusis AJ.
Endothelial responses to oxidized lipoproteins determine genetic
susceptibility to atherosclerosis in mice. Circulation 102: 75– 81,
2000.
Shih PT, Brennan ML, Vora DK, Territo MC, Strahl D, Elices
MJ, Lusis AJ, and Berliner JA. Blocking very late antigen-4
integrin decreases leukocyte entry and fatty streak formation in
mice fed an atherogenic diet. Circ Res 84: 345–351, 1999.
Shimada K, Watanabe Y, Mokuno H, Iwama Y, Daida H, and
Yamaguchi H. Common polymorphism in the promoter of the
CD14 monocyte receptor gene is associated with acute myocardial
infarction in Japanese men. Am J Cardiol 86: 682– 684, 2000.
Shindou H, Ishii S, Uozumi N, and Shimizu T. Roles of cytosolic
phospholipase A (2) and platelet-activating factor receptor in the
Ca-induced biosynthesis of PAF. Biochem Biophys Res Commun
271: 812– 817, 2000.
Siess W, Zangl KJ, Essler M, Bauer M, Brandl R, Corrinth C,
Bittman R, Tigyi G, and Aepfelbacher M. Lysophosphatidic acid
mediates the rapid activation of platelets and endothelial cells by
mildly oxidized low density lipoprotein and accumulates in human
atherosclerotic lesions. Proc Natl Acad Sci USA 96: 6931– 6936,
1999.
Silkworth JB, McLean B, and Stehbens WE. The effect of
hypercholesterolemia on aortic endothelium studied en face. Atherosclerosis 22: 335–348, 1975.
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
444. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med
340: 115–126, 1999.
445. Rot A, Krieger M, Brunner T, Bischoff SC, Schall TJ, and
Dahinden CA. RANTES and macrophage inflammatory protein 1
alpha induce the migration and activation of normal human eosinophil granulocytes. J Exp Med 176: 1489 –1495, 1992.
446. Rothe G, Gabriel H, Kovacs E, Klucken J, Stohr J, Kindermann W, and Schmitz G. Peripheral blood mononuclear phagocyte subpopulations as cellular markers in hypercholesterolemia.
Arterioscler Thromb Vasc Biol 16: 1437–1447, 1996.
447. Saitoh K, Mori T, Kasai H, Nagayama T, Tsuchiya A, and
Ohbayashi S. Anti-atheromatous effects of fenofibrate, a hypolipidemic drug. I. Anti-atheromatous effects are independent of its
hypolipidemic effect in cholesterol-fed rabbits. Nippon Yakurigaku
Zasshi 106: 41–50, 1995.
448. Sakaguchi H, Takeya M, Suzuki H, Hakamata H, Kodama T,
Horiuchi S, Gordon S, van der Laan LJ, Kraal G, Ishibashi S,
Kitamura N, and Takahashi K. Role of macrophage scavenger
receptors in diet-induced atherosclerosis in mice. Lab Invest 78:
423– 434, 1998.
450. Sakai M, Biwa T, Matsumura T, Takemura T, Matsuda H,
Anami Y, Sasahara T, Kobori S, and Shichiri M. Glucocorticoid
inhibits oxidized LDL-induced macrophage growth by suppressing
the expression of granulocyte/macrophage colony-stimulating factor. Arterioscler Thromb Vasc Biol 19: 1726 –1733, 1999.
451. Samuelsson B. The discovery of the leukotrienes. Am J Respir
Crit Care Med 161: S2–S6, 2000.
452. Sander HJ, Slot JW, Bouma BN, Bolhuis PA, Pepper DS, and
Sixma JJ. Immunocytochemical localization of fibrinogen, platelet
factor 4, and beta thromboglobulin in thin frozen sections of human
blood platelets. J Clin Invest 72: 1277–1287, 1983.
453. Sanz MJ, Johnston B, Issekutz A, and Kubes P. Endothelin-1
causes P-selectin-dependent leukocyte rolling and adhesion within
rat mesenteric microvessels. Am J Physiol Heart Circ Physiol 277:
H1823–H1830, 1999.
454. Sartipy P, Johansen B, Gasvik K, and Hurt-Camejo E. Molecular basis for the association of group IIA phospholipase A (2) and
decorin in human atherosclerotic lesions. Circ Res 86: 707–714,
2000.
455. Schall TJ, Bacon K, Toy KJ, and Goeddel DV. Selective attraction of monocytes and T lymphocytes of the memory phenotype by
cytokine RANTES. Nature 347: 669 – 671, 1990.
456. Schiering A, Menschikowski M, Mueller E, and Jaross W.
Analysis of secretory group II phospholipase A2 expression in
human aortic tissue in dependence on the degree of atherosclerosis. Atherosclerosis 144: 73–78, 1999.
457. Schievella AR, Regier MK, Smith WL, and Lin LL. Calciummediated translocation of cytosolic phospholipase A2 to the nuclear envelope and endoplasmic reticulum. J Biol Chem 270:
30749 –30754, 1995.
458. Schonbeck U, Sukhova GK, Graber P, Coulter S, and Libby P.
Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 155: 1281–1291, 1999.
459. Schonherr E and Hausser HJ. Extracellular matrix and cytokines: a functional unit. Dev Immunol 7: 89 –101, 2000.
460. Schoonjans K, Staels B, and Auwerx J. Role of the peroxisome
proliferator-activated receptor (PPAR) in mediating the effects of
fibrates and fatty acids on gene expression. J Lipid Res 37: 907–
925, 1996.
461. Schreyer SA, Peschon JJ, and LeBoeuf RC. Accelerated atherosclerosis in mice lacking tumor necrosis factor receptor p55. J Biol
Chem 271: 26174 –26178, 1996.
462. Schreyer SA, Vick CM, and LeBoeuf RC. Loss of lymphotoxinalpha but not tumor necrosis factor-alpha reduces atherosclerosis
in mice. J Biol Chem 277: 12364 –12368, 2002.
463. Schumann RR, Rietschel ET, and Loppnow H. The role of CD14
and lipopolysaccharide-binding protein (LBP) in the activation of
different cell types by endotoxin. Med Microbiol Immunol (Berl)
183: 279 –297, 1994.
464. Schwartz CJ, Sprague EA, Kelley JL, Valente AJ, and Suenram CA. Aortic intimal monocyte recruitment in the normo and
hypercholesterolemic baboon (Papio cynocephalus). An ultra-
1109
1110
BJARNE ØSTERUD AND EIRIK BJØRKLID
Physiol Rev • VOL
502. Stewart DJ. Impact of endothelin-1 on vascular structure and
function. Am J Cardiol 82: 14S–16S, 1998.
503. Stopeck AT, Nicholson AC, Mancini FP, and Hajjar DP. Cytokine regulation of low density lipoprotein receptor gene transcription in HepG2 cells. J Biol Chem 268: 17489 –17494, 1993.
504. Stormorken H and Sakariassen KS. Hemostatic risk factors in
arterial thrombosis and atherosclerosis: the thrombin-fibrin and
platelet-vWF axis. Thromb Res 88: 1–25, 1997.
505. Subbanagounder G, Leitinger N, Shih PT, Faull KF, and Berliner JA. Evidence that phospholipid oxidation products and/or
platelet-activating factor play an important role in early atherogenesis: in vitro and in vivo inhibition by WEB 2086. Circ Res 85:
311–318, 1999.
506. Sun D and Funk CD. Disruption of 12/15-lipoxygenase expression
in peritoneal macrophages. Enhanced utilization of the 5-lipoxygenase pathway and diminished oxidation of low density lipoprotein. J Biol Chem 271: 24055–24062, 1996.
507. Sun X, Rozenfeld RA, Qu X, Huang W, Gonzalez-Crussi F, and
Hsueh W. P-selectin-deficient mice are protected from PAF-induced shock, intestinal injury, and lethality. Am J Physiol Gastrointest Liver Physiol 273: G56 –G61, 1997.
508. Sun YP, Zhu BQ, Sievers RE, Isenberg WM, and Parmley WW.
Aspirin inhibits platelet activity but does not attenuate experimental atherosclerosis. Am Heart J 125: 79 – 86, 1993.
509. Suzuki H, Kurihara Y, Takeya M, Kamada N, Kataoka M,
Jishage K, Ueda O, Sakaguchi H, Higashi T, Suzuki T,
Takashima Y, Kawabe Y, Cynshi O, Wada Y, Honda M, Kurihara H, Aburatani H, Doi T, Matsumoto A, Azuma S, Noda T,
Toyoda Y, Itakura H, Yazaki Y, Honuchi S, Takahashi K, Kar
Kruijt J, van Berkel TJC, Steinbrecher UP, Ishibashi S,
Maeda N, Gordon S, and Kodama T. A role for macrophage
scavenger receptors in atherosclerosis and susceptibility to infection. Nature 386: 292–296, 1997.
510. Taga T, Narazaki M, Yasukawa K, Saito T, Miki D, Hamaguchi
M, Davis S, Shoyab M, Yancopoulos GD, and Kishimoto T.
Functional inhibition of hematopoietic and neurotrophic cytokines
by blocking the interleukin 6 signal transducer gp130. Proc Natl
Acad Sci USA 89: 10998 –11001, 1992.
511. Takahara N, Kashiwagi A, Maegawa H, and Shigeta Y. Lysophosphatidylcholine stimulates the expression and production of
MCP-1 by human vascular endothelial cells. Metabolism 45: 559 –
564, 1996.
512. Takahashi K, Nammour TM, Fukunaga M, Ebert J, Morrow
JD, Roberts LJ II, Hoover RL, and Badr KF. Glomerular actions
of a free radical-generated novel prostaglandin, 8-epi-prostaglandin
F2 alpha, in the rat. Evidence for interaction with thromboxane A2
receptors. J Clin Invest 90: 136 –141, 1992.
513. Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, and
Serhan CN. Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4
stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. J Exp Med 185: 1693–1704,
1997.
514. Takashiba S, Van Dyke TE, Amar S, Murayama Y, Soskolne
AW, and Shapira L. Differentiation of monocytes to macrophages
primes cells for lipopolysaccharide stimulation via accumulation of
cytoplasmic nuclear factor kappaB. Infect Immun 67: 5573–5578,
1999.
515. Takeya M, Yoshimura T, Leonard EJ, and Takahashi K. Detection of monocyte chemoattractant protein-1 in human atherosclerotic lesions by an anti-monocyte chemoattractant protein-1
monoclonal antibody. Hum Pathol 24: 534 –539, 1993.
516. Tatsuno I, Saito H, Chang KJ, Tamura Y, and Yoshida S.
Comparison of the effect between leukotriene B4 and leukotriene
B5 on the induction of interleukin 1-like activity and calcium mobilizing activity in human blood monocytes. Agents Actions 29:
324 –327, 1990.
517. Tau G and Rothman P. Biologic functions of the IFN-gamma
receptors. Allergy 54: 1233–1251, 1999.
518. Tedgui A and Mallat Z. Anti-inflammatory mechanisms in the
vascular wall. Circ Res 88: 877– 887, 2001.
519. Terkeltaub R, Banka CL, Solan J, Santoro D, Brand K, and
Curtiss LK. Oxidized LDL induces monocytic cell expression of
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
484. Simpson RJ, Hammacher A, Smith DK, Matthews JM, and
Ward LD. Interleukin-6: structure-function relationships. Protein
Sci 6: 929 –955, 1997.
485. Sisson SD and Dinarello CA. Production of interleukin-1 alpha,
interleukin-1 beta and tumor necrosis factor by human mononuclear cells stimulated with granulocyte-macrophage colony-stimulating factor. Blood 72: 1368 –1374, 1988.
486. Skrinska VA, Konieczkowski M, Gerrity RG, Galang CF, and
Rebec MV. Suppression of foam cell lesions in hypercholesterolemic rabbits by inhibition of thromboxane A2 synthesis. Arteriosclerosis 8: 359 –367, 1988.
487. Slupsky JR, Kalbas M, Willuweit A, Henn V, Kroczek RA, and
Muller-Berghaus G. Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of
CD40. Thromb Haemost 80: 1008 –1014, 1998.
488. Smith WB, Noack L, Khew-Goodall Y, Isenmann S, Vadas MA,
and Gamble JR. Transforming growth factor-beta 1 inhibits the
production of IL-8 and the transmigration of neutrophils through
activated endothelium. J Immunol 157: 360 –368, 1996.
489. Snitko Y, Yoon ET, and Cho W. High specificity of human secretory class II phospholipase A2 for phosphatidic acid. Biochem J
321: 737–741, 1997.
490. Solum NO. Procoagulant expression in platelets and defects leading to clinical disorders. Arterioscler Thromb Vasc Biol 19: 2841–
2846, 1999.
491. Song L, Leung C, and Schindler C. Lymphocytes are important in
early atherosclerosis. J Clin Invest 108: 251–259, 2001.
492. Sramek A, Reiber JH, Gerrits WB, and Rosendaal FR. Decreased coagulability has no clinically relevant effect on atherogenesis: observations in individuals with a hereditary bleeding
tendency. Circulation 104: 762–767, 2001.
493. Stack WA, Mann SD, Roy AJ, Heath P, Sopwith M, Freeman J,
Holmes G, Long R, Forbes A, and Kamm MA. Randomised
controlled trial of CDP571 antibody to tumour necrosis factoralpha in Crohn’s disease. Lancet 349: 521–524, 1997.
494. Staels B, Koenig W, Habib A, Merval R, Lebret M, Torra IP,
Delerive P, Fadel A, Chinetti G, Fruchart JC, Najib J, Maclouf J, and Tedgui A. Activation of human aortic smooth-muscle
cells is inhibited by PPARalpha but not by PPARgamma activators.
Nature 393: 790 –793, 1998.
495. Stary HC, Blankenhorn DH, Chandler AB, Glagov S, Insull W
Jr, Richardson M, Rosenfeld ME, Schaffer SA, Schwartz CJ,
and Wagner WD. A definition of the intima of human arteries and
of its atherosclerosis-prone regions. A report from the Committee
on Vascular Lesions of the Council on Arteriosclerosis, American
Heart Association. Circulation 85: 391– 405, 1992.
496. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S,
Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, and
Wissler RW. A definition of advanced types of atherosclerotic
lesions and a histological classification of atherosclerosis. A report
from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 92: 1355–
1374, 1995.
497. Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W Jr,
Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD, and
Wissler RW. A definition of initial, fatty streak, and intermediate
lesions of atherosclerosis A report from the Committee on Vascular
Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 89: 2462–2478, 1994.
498. Steel DJ, Tieman TL, Schwartz JH, and Feinmark SJ. Identification of an 8-lipoxygenase pathway in nervous tissue of Aplysia
californica. J Biol Chem 272: 18673–18681, 1997.
499. Steinberg Lewis AD. Conner Memorial Lecture. Oxidative modification of LDL and atherogenesis. Circulation 95: 1062–1071, 1997.
500. Stengel D, Antonucci M, Gaoua W, Dachet C, Lesnik P, Hourton D, Ninio E, Chapman MJ, and Griglio S. Inhibition of LPL
expression in human monocyte-derived macrophages is dependent
on LDL oxidation state: a key role for lysophosphatidylcholine.
Arterioscler Thromb Vasc Biol 18: 1172–1180, 1998.
501. Stewart AG, Harris T, De Nichilo M, and Lopez AF. Involvement of leukotriene B4 and platelet-activating factor in cytokine
priming of human polymorphonuclear leucocytes. Immunology 72:
206 –212, 1991.
MONOCYTES IN ATHEROGENESIS
520.
521.
522.
523.
525.
526.
527.
528.
529.
530.
531.
532.
533.
534.
535.
536.
537.
Physiol Rev • VOL
538.
539.
540.
541.
542.
543.
544.
545.
546.
547.
548.
549.
550.
551.
552.
553.
554.
555.
556.
kocyte and platelet lipoxygenases by hydroxyeicosanoids. Biochem Pharmacol 31: 3463–3467, 1982.
Van der Poll T, Levi M, Hack CE, ten Cate H, van Deventer SJ,
Eerenberg AJ, de Groot ER, Jansen J, Gallati H, Buller HR,
ten Cate JW, and Aarden L. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 179: 1253–1259, 1994.
Van Diest MJ, Herman AG, and Verbeuren TJ. Influence of
hypercholesterolaemia on the reactivity of isolated rabbit arteries
to 15-lipoxygenase metabolites of arachidonic acid: comparison
with platelet-derived agents and vasodilators. Prostaglandins Leukotrienes Essent Fatty Acids 54: 135–145, 1996.
Van Kooten C, and Banchereau J. CD40-CD40 ligand. J Leukoc
Biol 67: 2–17, 2000.
Vane JR, Bakhle YS, and Botting RM. Cyclooxygenases 1 and 2.
Annu Rev Pharmacol Toxicol 38: 97–120, 1998.
Viedt C, Vogel J, Athanasiou T, Shen W, Orth SR, Kubler W,
and Kreuzer J. Monocyte chemoattractant protein-1 induces proliferation and interleukin-6 production in human smooth muscle
cells by differential activation of nuclear factor-kappaB and activator protein-1. Arterioscler Thromb Vasc Biol 22: 914 –920, 2002.
Von Hundelshausen P, Weber KS, Huo Y, Proudfoot AE, Nelson PJ, Ley K, and Weber C. RANTES deposition by platelets
triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 103: 1772–1777, 2001.
Waage A and Bakke O. Glucocorticoids suppress the production
of tumour necrosis factor by lipopolysaccharide-stimulated human
monocytes. Immunology 63: 299 –302, 1988.
Waage A, Brandtzaeg P, Halstensen A, Kierulf P, and Espevik
T. The complex pattern of cytokines in serum from patients with
meningococcal septic shock. Association between interleukin 6,
interleukin 1, and fatal outcome. J Exp Med 169: 333–338, 1989.
Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell
Biol 6: 217–246, 1990.
Wahl SM, McCartney-Francis N, Allen JB, Dougherty EB, and
Dougherty SF. Macrophage production of TGF-beta and regulation by TGF-beta. Ann NY Acad Sci 593: 188 –196, 1990.
Wahli W, Braissant O, and Desvergne B. Peroxisome proliferator activated receptors: transcriptional regulators of adipogenesis,
lipid metabolism and more. Chem Biol 2: 261–266, 1995.
Walker LN, Reidy MA, and Bowyer DE. Morphology and cell
kinetics of fatty streak lesion formation in the hypercholesterolemic rabbit. Am J Pathol 125: 450 – 459, 1986.
Wang N, Tabas I, Winchester R, Ravalli S, Rabbani LE, and
Tall A. Interleukin 8 is induced by cholesterol loading of macrophages and expressed by macrophage foam cells in human atheroma. J Biol Chem 271: 8837– 8842, 1996.
Wang X, Reape TJ, Li X, Rayner K, Webb CL, Burnand KG,
and Lysko PG. Induced expression of adipophilin mRNA in human
macrophages stimulated with oxidized low-density lipoprotein and
in atherosclerotic lesions. FEBS Lett 462: 145–150, 1999.
Watanabe T and Fan J. Atherosclerosis and inflammation mononuclear cell recruitment and adhesion molecules with reference to
the implication of ICAM-1/LFA-1 pathway in atherogenesis. Int
J Cardiol 66 Suppl 1: S45–S55, 1998.
Watson AD, Berliner JA, Hama SY, La Du BN, Faull KF,
Fogelman AM, and Navab M. Protective effect of high density
lipoprotein associated paraoxonase. Inhibition of the biological
activity of minimally oxidized low density lipoprotein. J Clin Invest
96: 2882–2891, 1995.
Watson AD, Navab M, Hama SY, Sevanian A, Prescott SM,
Stafforini DM, McIntyre TM, Du BN, Fogelman AM, and Berliner JA. Effect of platelet activating factor-acetylhydrolase on the
formation and action of minimally oxidized low density lipoprotein.
J Clin Invest 95: 774 –782, 1995.
Wayner EA, Garcia-Pardo A, Humphries MJ, McDonald JA,
and Carter WG. Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin. J Cell Biol 109: 1321–1330, 1989.
Weber KS, von Hundelshausen P, Clark-Lewis I, Weber PC,
and Weber C. Differential immobilization and hierarchical involvement of chemokines in monocyte arrest and transmigration
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
524.
interleukin-8, a chemokine with T-lymphocyte chemotactic activity. Arterioscler Thromb 14: 47–53, 1994.
Tesfamariam B, Brown ML, and Cohen RA. 15-Hydroxyeicosatetraenoic acid and diabetic endothelial dysfunction in rabbit aorta.
J Cardiovasc Pharmacol 25: 748 –755, 1995.
Theilmeier G, Michiels C, Spaepen E, Vreys I, Collen D, Vermylen J, and Hoylaerts MF. Endothelial von Willebrand factor
recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia. Blood 99: 4486 – 4493, 2002.
Thivierge M, Alami N, Muller E, de Brum-Fernandes AJ, and
Rola-Pleszczynski M. Transcriptional modulation of platelet-activating factor receptor gene expression by cyclic AMP. J Biol Chem
268: 17457–17462, 1993.
Thomas DW, Mannon RB, Mannon PJ, Latour A, Oliver JA,
Hoffman M, Smithies O, Koller BH, and Coffman TM. Coagulation defects and altered hemodynamic responses in mice lacking
receptors for thromboxane A2. J Clin Invest 102: 1994 –2001, 1998.
Thommesen L, Sjursen W, Gasvik K, Hanssen W, Brekke OL,
Skattebol L, Holmeide AK, Espevik T, Johansen B, and Laegreid A. Selective inhibitors of cytosolic or secretory phospholipase A2 block TNF-induced activation of transcription factor nuclear factor-kappa B and expression of ICAM-1. J Immunol 161:
3421–3430, 1998.
Tilg H, Trehu E, Atkins MB, Dinarello CA, and Mier JW.
Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of
circulating IL-1 receptor antagonist and soluble tumor necrosis
factor receptor p55. Blood 83: 113–118, 1994.
Tischfield JA. A reassessment of the low molecular weight phospholipase A2 gene family in mammals. J Biol Chem 272: 17247–
17250, 1997.
Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, and Evans RM.
PPARgamma promotes monocyte/macrophage differentiation and
uptake of oxidized LDL. Cell 93: 241–252, 1998.
Tracy RP. Epidemiological evidence for inflammation in cardiovascular disease. Thromb Haemost 82: 826 – 831, 1999.
Trigatti B, Rayburn H, Vinals M, Braun A, Miettinen H, Penman M, Hertz M, Schrenzel M, Amigo L, Rigotti A, and
Krieger M. Influence of the high density lipoprotein receptor
SR-BI on reproductive and cardiovascular pathophysiology. Proc
Natl Acad Sci USA 96: 9322–9327, 1999.
Tsuji T, Nagata K, Koike J, Todoroki N, and Irimura T. Induction of superoxide anion production from monocytes and neutrophils by activated platelets through the P-selectin-sialyl Lewis X
interaction. J Leukoc Biol 56: 583–587, 1994.
Tuttle DL, Harrison JK, Anders C, Sleasman JW, and Goodenow MM. Expression of CCR5 increases during monocyte differentiation and directly mediates macrophage susceptibility to infection by human immunodeficiency virus type 1. J Virol 72: 4962–
4969, 1998.
Uguccioni M, D’Apuzzo M, Loetscher M, Dewald B, and Baggiolini M. Actions of the chemotactic cytokines MCP-1, MCP-2,
MCP-3, RANTES, MIP-1 alpha and MIP-1 beta on human monocytes. Eur J Immunol 25: 64 – 68, 1995.
Unkelbach K, Gardemann A, Kostrzewa M, Philipp M, Tillmanns H, and Haberbosch W. A new promoter polymorphism in
the gene of lipopolysaccharide receptor CD14 is associated with
expired myocardial infarction in patients with low atherosclerotic
risk profile. Arterioscler Thromb Vasc Biol 19: 932–938, 1999.
Uozumi N, Kume K, Nagase T, Nakatani N, Ishii S, Tashiro F,
Komagata Y, Maki K, Ikuta K, Ouchi Y, Miyazaki J, and
Shimizu T. Role of cytosolic phospholipase A2 in allergic response
and parturition. Nature 390: 618 – 622, 1997.
Upston JM, Neuzil J, Witting PK, Alleva R, and Stocker R.
Oxidation of free fatty acids in low density lipoprotein by 15lipoxygenase stimulates nonenzymic, alpha-tocopherol-mediated
peroxidation of cholesteryl esters. J Biol Chem 272: 30067–30074,
1997.
Vanderhoek JY, Bryant RW, and Bailey JM. Inhibition of leukotriene biosynthesis by the leukocyte product 15-hydroxy5,8,11,13-eicosatetraenoic acid. J Biol Chem 255: 10064 –10066,
1980.
Vanderhoek JY, Bryant RW, and Bailey JM. Regulation of leu-
1111
1112
557.
558.
559.
560.
562.
563.
564.
565.
566.
567.
568.
569.
570.
571.
572.
573.
on inflamed endothelium in shear flow. Eur J Immunol 29: 700 –
712, 1999.
Weijenberg MP, Feskens EJ, and Kromhout D. White blood cell
count and the risk of coronary heart disease and all-cause mortality
in elderly men. Arterioscler Thromb Vasc Biol 16: 499 –503, 1996.
Wesley RB II, Meng X, Godin D, and Galis ZS. Extracellular
matrix modulates macrophage functions characteristic to atheroma: collagen type I enhances acquisition of resident macrophage
traits by human peripheral blood monocytes in vitro. Arterioscler
Thromb Vasc Biol 18: 432– 440, 1998.
Weyrich AS, Elstad MR, McEver RP, McIntyre TM, Moore KL,
Morrissey JH, Prescott SM, and Zimmerman GA. Activated
platelets signal chemokine synthesis by human monocytes. J Clin
Invest 97: 1525–1534, 1996.
Weyrich AS, McIntyre TM, McEver RP, Prescott SM, and
Zimmerman GA. Monocyte tethering by P-selectin regulates
monocyte chemotactic protein-1 and tumor necrosis factor-alpha
secretion. Signal integration and NF-kappa B translocation. J Clin
Invest 95: 2297–2303, 1995.
Whitman SC, Ravisankar P, and Daugherty A. Interleukin-18
enhances atherosclerosis in apolipoprotein E (⫺/⫺) mice through
release of interferon-gamma. Circ Res 90: E34 –E38, 2002.
Whitman SC, Ravisankar P, Elam H, and Daugherty A. Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E⫺/⫺ mice. Am J Pathol 157: 1819 –1824, 2000.
Wilcox JN, Nelken NA, Coughlin SR, Gordon D, and Schall TJ.
Local expression of inflammatory cytokines in human atherosclerotic plaques. J Atheroscler Thromb 1: S10 –S13, 1994.
Williams CS and DuBois RN. Prostaglandin endoperoxide synthase: why two isoforms? Am J Physiol Gastrointest Liver Physiol
270: G393–G400, 1996.
Williams KJ and Tabas I. The response-to-retention hypothesis of
early atherogenesis. Arterioscler Thromb Vasc Biol 15: 551–561,
1995.
Winsor GL, Waterhouse CC, MacLellan RL, and Stadnyk AW.
Interleukin-4 and IFN-gamma differentially stimulate macrophage
chemoattractant protein-1 (MCP-1) and eotaxin production by intestinal epithelial cells. J Interferon Cytokine Res 20: 299 –308,
2000.
Wintergerst ES, Jelk J, and Asmis R. Differential expression of
CD14, CD36 and the LDL receptor on human monocyte-derived
macrophages. A novel cell culture system to study macrophage
differentiation and heterogeneity. Histochem Cell Biol 110: 231–
241, 1998.
Witztum JL and Steinberg D. Role of oxidized low density
lipoprotein in atherogenesis. J Clin Invest 88: 1785–1792, 1991.
Wolbink GJ, Bossink AW, Groeneveld AB, de Groot MC, Thijs
LG, and Hack CE. Complement activation in patients with sepsis
is in part mediated by C-reactive protein. J Infect Dis 177: 81– 87,
1998.
Woods JW, Coffey MJ, Brock TG, Singer II, and PetersGolden M. 5-Lipoxygenase is located in the euchromatin of the
nucleus in resting human alveolar macrophages and translocates to
the nuclear envelope upon cell activation. J Clin Invest 95: 2035–
2046, 1995.
Xu Q, Willeit J, Marosi M, Kleindienst R, Oberhollenzer F,
Kiechl S, Stulnig T, Luef G, and Wick G. Association of serum
antibodies to heat-shock protein 65 with carotid atherosclerosis.
Lancet 341: 255–259, 1993.
Yamaguchi H, Haranaga S, Widen R, Friedman H, and
Yamamoto Y. Chlamydia pneumoniae infection induces differentiation of monocytes into macrophages. Infect Immun 70: 2392–
2398, 2002.
Yamaguchi Y, Matsumura F, Liang J, Okabe K, Ohshiro H,
Physiol Rev • VOL
574.
575.
577.
578.
579.
580.
581.
582.
583.
584.
585.
586.
587.
588.
589.
590.
591.
Ishihara K, Matsuda T, Mori K, and Ogawa M. Neutrophil
elastase and oxygen radicals enhance monocyte chemoattractant
protein-expression after ischemia/reperfusion in rat liver. Transplantation 68: 1459 –1468, 1999.
Yamamoto S. “Enzymatic” lipid peroxidation: reactions of mammalian lipoxygenases. Free Radic Biol Med 10: 149 –159, 1991.
Yamamoto S. Mammalian lipoxygenases: molecular structures
and functions. Biochim Biophys Acta 1128: 117–131, 1992.
Yamamoto S, Suzuki H, and Ueda N. Arachidonate 12-lipoxygenases. Prog Lipid Res 36: 23– 41, 1997.
Yang J, Furie BC, and Furie B. The biology of P-selectin glycoprotein ligand-1: its role as a selectin counterreceptor in leukocyteendothelial and leukocyte-platelet interaction. Thromb Haemost
81: 1–7, 1999.
Yesner LM, Huh HY, Pearce SF, and Silverstein RL. Regulation
of monocyte CD36 and thrombospondin-1 expression by soluble
mediators. Arterioscler Thromb Vasc Biol 16: 1019 –1025, 1996.
Yin K, Halushka PV, Yan YT, and Wong PY. Antiaggregatory
activity of 8-epi-prostaglandin F2 alpha and other F-series prostanoids and their binding to thromboxane A2/prostaglandin H2 receptors in human platelets. J Pharmacol Exp Ther 270: 1192–1196,
1994.
Yin T, Taga T, Tsang ML, Yasukawa K, Kishimoto T, and Yang
YC. Involvement of IL-6 signal transducer gp130 in IL-11-mediated
signal transduction. J Immunol 151: 2555–2561, 1993.
Yla-Herttuala S, Lipton BA, Rosenfeld ME, Sarkioja T, Yoshimura T, Leonard EJ, Witztum JL, and Steinberg D. Expression of monocyte chemoattractant protein 1 in macrophage-rich
areas of human and rabbit atherosclerotic lesions. Proc Natl Acad
Sci USA 88: 5252–5256, 1991.
Yla-Herttuala S, Palinski W, Butler SW, Picard S, Steinberg
D, and Witztum JL. Rabbit and human atherosclerotic lesions
contain IgG that recognizes epitopes of oxidized LDL. Arterioscler
Thromb 14: 32– 40, 1994.
Yla-Herttuala S, Rosenfeld ME, Parthasarathy S, Sigal E,
Sarkioja T, Witztum JL, and Steinberg D. Gene expression in
macrophage-rich human atherosclerotic lesions. 15-Lipoxygenase
and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts. J Clin Invest
87: 1146 –1152, 1991.
Yokomizo T, Izumi T, Chang K, Takuwa Y, and Shimizu T. A
G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 387: 620 – 624, 1997.
Young RA and Elliott TJ. Stress proteins, infection, and immune
surveillance. Cell 59: 5– 8, 1989.
Zeindler CM, Kratky RG, and Roach MR. Quantitative measurements of early atherosclerotic lesions on rabbit aortae from vascular casts. Atherosclerosis 76: 245–255, 1989.
Zibara K, Chignier E, Covacho C, Poston R, Canard G, Hardy
P, and McGregor J. Modulation of expression of endothelial
intercellular adhesion molecule-1, platelet-endothelial cell adhesion molecule-1, and vascular cell adhesion molecule-1 in aortic
arch lesions of apolipoprotein E-deficient compared with wild-type
mice. Arterioscler Thromb Vasc Biol 20: 2288 –2296, 2000.
Zimmerman G. Inflammation: Basic Principles and Clinical Correlates (2nd ed.). New York: Raven, 1992, p. 149.
Zouki C, Beauchamp M, Baron C, and Filep JG. Prevention of
in vitro neutrophil adhesion to endothelial cells through shedding
of L-selectin by C-reactive protein and peptides derived from C-reactive protein. J Clin Invest 100: 522–529, 1997.
Zwaka TP, Hombach V, and Torzewski J. C-reactive proteinmediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation 103: 1194 –1197, 2001.
83 • OCTOBER 2003 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on July 4, 2017
561.
BJARNE ØSTERUD AND EIRIK BJØRKLID