See related article, pages 1245–1252
Endothelial Cell IL-8, a New Target for Adiponectin
Implications in Vascular Protection
Rhian M. Touyz
A
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cytes, but also by human and murine cardiomyocytes21 and
hepatocytes.22 It is a multifunctional protein with protective
roles against the development of insulin resistance, dyslipidemia, nonalcoholic fatty liver disease, atherosclerosis, cardiac
hypertrophy, and ischemic injury.23,24 These actions are
mediated in large part through the antiinflammatory properties of adiponectin. However, the understanding of the molecular mechanisms whereby adiponectin achieves these effects is still poor, and there is still much debate as to whether
adiponectin is indeed an antiinflammatory hormone or merely
a modulator of innate immunity.25
Kobashi and colleagues, in this issue of Circulation
Research, attempt to unravel some of the molecular mysteries
underlying adiponectin actions by studying effects of human
recombinant adiponectin on IL-8 production in TNF-␣–
stimulated human endothelial cells.26 It is demonstrated that
some of the antiinflammatory properties of adiponectin occur
through inhibition of endothelial TNF-␣–induced IL-8 formation. These are not novel findings, except with the caveat
that observations were made in endothelial cells. Other
studies demonstrated that adiponectin reduces production and
activity of TNF-␣ in various cell types.27 Interestingly, in
adipocytes, adiponectin production itself is downregulated by
TNF-␣.28,29 Hence TNF-␣ appears to be both upstream and
downstream of adiponectin. The antiinflammatory activities
of adiponectin extend to inhibition of IL-6 synthesis and
induction of antiinflammatory cytokines IL-10 and IL-1. By
downregulating expression of vascular cell adhesion
molecule-1, E-selectin, and intercellular adhesion molecule
(ICAM-1), adiponectin suppresses adherence of monocytes
and platelets to the endothelium, thereby negatively modulating the proatherogenic process.30
Kobashi et al show that adiponectin also downregulates
IL-8.26 But why focus on IL-8? IL-8, or CXCL8, is a
chemokine initially characterized for its leukocyte chemotactic activity but now known to possess tumorigenic, proangiogenic, proinflammatory, and proatherogenic properties as
well.31,32 Interleukin-8 plays a causative role in acute inflammation by recruiting and activating neutrophils.32 It also
promotes vascular smooth muscle cell proliferation and
migration and is critical for chemotaxis and adhesion of
monocytes to endothelial cells, a pivotal step in the initiation
of atherogenesis.33,34 In addition, circulating levels of these
proinflammatory cytokines increase in patients with acute
myocardial infarction and unstable angina.35 Il-8 is upregulated in the infarcted area and induces neutrophil infiltration
and inflammation. Hence inhibition of IL-8 by adiponectin
may have important antiinflammatory, antiatherogenic, and
cardiovascular protective effects.
dipose tissue is no longer considered an inert energy
storage tissue, but an active participant contributing
to physiological and pathological processes associated with inflammation, immunity, appetite, insulin sensitivity, endocrine and reproductive systems, bone metabolism,
and endothelial function.1,2 Adipose tissue synthesizes and
secretes proinflammatory and antiinflammatory metabolically- and hormonally-active substances, collectively called
adipokines or adipocytokines and include leptin, adiponectin,
resistin, and visfatin.3,4 Adipose tissue also produces cytokines and chemokines, such as tissue necrosis factor (TNF)1␣, interleukin (IL)-1␤, IL-6, IL-8, IL-10, transforming
growth factor (TGF)-␤, nerve growth factor and the acutephase response plasminogen activator inhibitor-1, haptoglobin, and serum amyloid.1,2,5 Although adipose tissue produces
various polypeptide and non-protein factors, only leptin,
adiponectin, resistin, adipsin, and visfatin are primarily synthesized by adipocytes.3,4 Whereas leptin plays a role mainly
in appetite regulation,6 resistin induces insulin resistance and
is proinflammatory7 whereas visfatin acts as an insulinmimetic and is antiapoptotic.8
Of all the adipokines, adiponectin is found in highest
concentrations in the circulation.9 It is secreted specifically
from adipocytes and it regulates insulin sensitivity.10 Low
serum levels are causally linked to insulin resistance, obesity,
and type 2 diabetes and are predictive for development of
diabetes and cardiovascular disease.11,12 Obesity is associated
with decreased adiponectin levels, and adiponectin is now
being considered a putative therapeutic agent in the management of obesity.13,14 Administration of adiponectin causes
glucose-lowering effects and ameliorates insulin resistance in
mice.15,16 Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes.17,18 This insulin-sensitizing
effect of adiponectin seems to be mediated by an increase in
fatty-acid oxidation through activation of AMP kinase19 and
peroxisome proliferator-activated receptor-␥ (PPAR-␥).20
Emerging evidence indicates that adiponectin has functions
beyond insulin modulation. Recent studies demonstrated that
adiponectin is synthesized and secreted not only by adipoThe opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Kidney Research Centre, University of Ottawa, Ontario,
Canada.
Correspondence to Rhian M. Touyz, MD, PhD, Canada Research
Chair in Hypertension, Kidney Research Centre, OHRI/University of
Ottawa, Room 303, 451 Smyth Rd, Ottawa, K1H 8M5. E-mail
[email protected]
(Circ Res. 2005;97:1216 –1219.)
© 2005 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/01.RES.0000196745.09234.36
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Touyz
IL-1 and Adiponectin
1217
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Possible molecular mechanisms whereby
adiponectin negatively regulates endothelial cell production of IL-8. TNF␣ activates nuclear transcription factor NF-␬B
by stimulating protein kinase NIK (NF␬B-inducing kinase), which phosphorylates the NF-␬B inhibitor I␬B, initiating its
degradation and hence leading to NF-␬B
activation. NF-␬B stimulates expression
of IL-8. Adiponectin inhibits TNF-␣–
dependent phosphorylation and degradation of I␬B. Inhibition of I␬B phosphorylation occurs through the cAMP-protein
kinase A (PKA) pathway. Adiponectin
may also inhibit IL-8 synthesis by stimulating phosphorylation and activation of
Akt. Transmembrane mechanisms
whereby adiponectin mediates signaling
events are unclear, and to date it is
unknown whether endothelial cells possess functionally active adiponectin
receptors, AdipoRI and AdipoRII. ⫺ indicates inhibitory effect; arrows, stimulatory effects; p, phosphorylated state.
However, what still remains unclear is the signaling
network underlying the inhibitory effects of adiponectin on
TNF-␣ and how it attenuates IL-8 synthesis. Kobashi et al
elegantly demonstrate that adiponectin modulates the inflammatory response to TNF-␣ by inhibiting NF-␬B, a proinflammatory transcription factor, through decreased phosphorylation of I␬B, which normally induces activation and nuclear
translocation of N-F␬B.26 This inhibitory effect is accomplished through protein kinase A (PKA)-dependent pathways,
because PKA inhibition abrogated adiponectin-mediated inhibition of TNF-␣ actions. Similar findings were reported by
Ouchi et al who demonstrated that adiponectin inhibits
TNF-␣– dependent phosphorylation and degradation of I␬B
through a cAMP–PKA-sensitive pathway.36 In addition,
Kobashi et al show that adiponectin reduces IL-8 generation
through activation of PI3K-sensitive pathways by enhancing
Akt phosphorylation.26 Pharmacological inhibition of PI3
kinase and siRNA silencing of Akt attenuated adiponectininduced Akt activation and TNF-␣– elicited IL-8 synthesis,
thus identifying a second mechanism for adiponectin–IL-8
effects. Taken together these findings suggest that IL-8 –
mediated antiinflammatory actions of adiponectin involve
two distinct processes. Firstly through PKA-regulated inhibition of NF-␬B, and secondly through activation of PI3
kinase/Akt, a well-established cell survival pathway (Figure).
The study of Kobashi and colleagues certainly expands our
knowledge explaining some mechanisms by which adiponectin negatively modulates IL-8 and inflammatory responses.26
However, a few thought-provoking questions and limitations
of the study arise that warrant further consideration. Firstly,
what is the clinical significance of an adipokine that is
produced by adipose tissue that may be physically unrelated
to endothelial cells? Histological examination has shown that
perivascular white adipose tissue is actually in very close
proximity to vascular walls, particularly at sites that have a
tendency to develop atherosclerosis. Henrichot et al demonstrated that at a functional level, supernatant from subcutaneous and perivascular white fat strongly induced chemotaxis
of peripheral blood leukocytes.37 The migration of granulocytes and monocytes was mediated primarily by IL-8 and
MCP-1, respectively, whereas both chemokines contributed
to the migration of activated T cells. Moreover, human
perivascular white adipose tissue produces IL-8 as shown by
immunohistochemistry and by explant culture.37 Accumulation of macrophages and T cells at the interface between
adipose tissue and the vascular wall may thus reflect a
prochemotactic activity of adipocyte-derived adiponectin,
supporting an important relationship between adipose tissue
and vascular cells.
Secondly, how does adiponectin mediate signaling events
in endothelial cells? Recently, cloning of adiponectin receptors I and II (adipoRI and adipoRII) was reported.38 Whereas
in mice adipoRI is abundantly expressed in skeletal muscle,
adipoRII is predominantly expressed in the liver.22 HL-1 cells
(a cultured line derived from murine atrial cardiomyocytes
and cultured human cardiomyocytes) have also been shown
to express genes for AdipoRI and AdipoRII.21 These receptors are predicted to contain 7 transmembrane domains but
are structurally, topologically, and functionally distinct from
GPCRs.22,38 They do not seem to be coupled with G protein
but activate unique sets of signaling molecules such as
PPAR-␣, AMPK, and p38 MAPK.38 Thus, adiponectin receptors may comprise a new receptor family. Whether vascular cells, and particularly endothelial cells, express adiponectin receptors I and II is unknown. It would have been
interesting and important for Kobashi’s group to demonstrate
that AdipoRI and AdipoRII are present and functionally
active in their experimental paradigm of human aortic endo-
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December 9/23, 2005
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thelial cells. Unfortunately these data are lacking and therefore it still remains unclear as to how adiponectin modulates
TNF-␣/NF-␬B/Akt/IL-8 signaling in endothelial cells. Hopefully these aspects will be clarified in future studies.
In the study under review in this journal,26 it is suggested
that the inhibitory effects of adiponectin may have beneficial
antiinflammatory and antiatherogenic actions. However, one
should keep in mind that the experiments were performed in
cultured cells that were highly passaged (passages 8 to 12), in
the absence of adipocytes, in acutely stimulated conditions
using nonspecific pharmacological tools to manipulate signaling molecules. Although such in vitro studies are necessary and essential to dissect out complex signaling pathways,
caution should be exercised when extrapolating findings from
such an artificial setting to in vivo conditions to explain how
atherosclerosis develops in humans.
Nevertheless, despite the limitations of the study, we have
learned that endothelial cells are regulated by adiponectin,
that adiponectin inhibits TNF-␣–mediated IL-8 synthesis, and
that multiple signaling pathways are involved in adiponectininduced actions. Whether these findings will have (patho)physiological significance in the regulation of endothelial
function in intact vessels and whether these processes contribute to antiinflammatory and antiatherogenic actions of
adiponectin in pathological conditions associated with atherosclerosis and vascular disease remain to be elucidated.
Acknowledgments
13.
14.
15.
16.
17.
18.
19.
20.
21.
Dr Touyz is supported by grants from the Canadian Institutes of
Health Research and the Heart and Stroke Foundation of Canada.
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KEY WORDS: inflammation
䡲 TNF-␣
䡲
adipokines
䡲
interleukin
䡲
endothelium
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Endothelial Cell IL-8, a New Target for Adiponectin: Implications in Vascular Protection
Rhian M. Touyz
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
Circ Res. 2005;97:1216-1219
doi: 10.1161/01.RES.0000196745.09234.36
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