Granulocyte Macrophage–Colony Stimulating Factor Increases
the Expression of Histamine and Histamine Receptors in
Monocytes/Macrophages in Relation to Arteriosclerosis
Yoshitaka Murata, Akihide Tanimoto, Ke-Yong Wang, Masato Tsutsui, Yasuyuki Sasaguri,
Filip De Corte, Hiroshi Matsushita
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Objective—To study the effect of granulocyte macrophage– colony-stimulating factor (GM-CSF) on histamine metabolism
in arteriosclerosis, the expression of histidine decarboxylase (HDC; histamine-producing enzyme), histamine receptors
1 and 2 (HH1R and HH2R), and GM-CSF was investigated in human and mouse arteriosclerotic carotid arteries.
Furthermore, the molecular mechanisms of GM-CSF–induced HDC and HH1R expression in monocytic U937 cells
were investigated.
Methods and Results—Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid
arteries contained HDC-expressing macrophages. Gene expression of HDC, HH1R, HH2R, and GM-CSF was also
detected in the lesions. In U937 cells, GM-CSF enhanced histamine secretion and gene expression of HDC and HH1R.
A promoter assay showed that GM-CSF enhanced gene transcription of HDC and HH1R but not HH2R.
Conclusion—The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion, and that GM-CSF
induces HDC and HH1R expression in monocytes. Locally produced histamine might participate in atherogenesis by
affecting the expression of atherosclerosis-related genes in monocytes and smooth muscle cells. (Arterioscler Thromb
Vasc Biol. 2005;25:430-435.)
Key Words: monocyte/macrophage 䡲 histamine 䡲 histidine decarboxylase 䡲 histamine receptor 䡲 atherosclerosis
H
In atheromatous plaques, macrophages are the most abundant cells expressing granulocyte macrophage– colonystimulating factor (GM-CSF),11 which is a macrophage differentiation and proliferation factor,12 and therefore an
atherogenic cytokine.13 We already demonstrated1 that HDC
shows a distribution similar to that of GM-CSF in macrophages. However, no study has evaluated the association
between histamine and GM-CSF. Here we demonstrated that
HDC and HH1R expression are upregulated by GM-CSF at
the transcriptional level partly through c-Fos/c-Jun–related
mechanisms, and that human advanced atherosclerotic lesion
and mouse arteriosclerotic lesion express GM-CSF, HDC,
HH1R, and HH2R genes.
istidine decarboxylase (HDC) is a rate-limiting enzyme for
production of histamine from L-histidine. Expression of
HDC is observed in many types of cells including mast cells,
T-lymphocytes, monocytes/macrophages, enterochromaffin-like
cells, and neuroendocrine cells,1–3 thereby playing an important
role in allergy, inflammation, neurotransmission, and gastrointestinal functions via specific histamine receptors (HHRs) that
are classified into H1, H2, H3, and H4 types.4,5
We demonstrated previously that HDC is expressed in the
macrophages of human atherosclerotic lesions.1 In U937
monocytes, expression of HDC and histamine H1 and H2
receptors (HH1R, HH2R) is regulated during macrophage
differentiation.6 In endothelial cells (ECs), histamine induces
expression of P-selectin and endothelial NO synthase via
HH1R,7,8 which is expressed in ECs and smooth muscle cells
(SMCs) of human atherosclerotic lesion.9 Histamine also
stimulates SMCs to proliferate and to express matrix
metalloproteinase-1 (MMP-1).10 These findings suggest that
histamine plays important roles in the functions of monocytes, ECs, and SMCs. However, up to now, no physiological
factor(s) regulating the expression of histamine and its
receptors in monocytes/macrophages has been demonstrated.
Materials and Methods
Immunolocalization of HDC in Human
Carotid Artery
Tissues obtained by carotid intimectomy were used for immunohistochemistry2 after fixation in 10% formalin and embedding in
paraffin. Sections were then cut and immunostained using rabbit
polyclonal anti-HDC antibody (dilution 1:500; PROGEN Biotech-
Original received November 13, 2003; final version accepted October 3, 2004.
From the Kyurin Omtest Laboratory (Y.M.), Kyurin Corporation, Yahatanishi-ku, Kitakyushu, the Department of Pathology (A.T., H.M.), Toranomon
Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, and the Departments of Pathology and Cell Biology (A.T., K.-Y.W., Y.S.) and
Pharmacology (M.T.), School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan; and Johnson and
Johnson Pharmaceuticals Group (F.D.), Licensing and New Business Development, Beerse, Belgium.
Correspondence to Akihide Tanimoto, MD, PhD, Department of Pathology, Toranomon Hospital and Okinaka Memorial Institute for Medical
Research, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan. E-mail [email protected]
© 2005 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
430
DOI: 10.1161/01.ATV.0000148705.13411.65
Murata et al
GM-GSF Regulation of Histamine
431
nik), mouse monoclonal anti-CD68 antibody (dilution 1:100;
DAKO), and anti–␣-smooth muscle actin (␣-SMA; dilution 1:1;
DAKO).
Mouse Carotid Ligation
Experiments were performed in 8-week-old male C57BL/6J mice
(20 to 25 g). Mice were anesthetized with pentobarbital (50 mg/kg
IP), and the left common carotid artery was ligated with a 6-0 silk
suture at the site just proximal to the carotid bifurcation. Mice were
euthanized by an overdose of pentobarbital (intraperitoneally) at 3
weeks after carotid ligation.14 The aorta was perfused with 10%
formalin, and the ligated carotid arteries were resected. Paraffin
sections (5-␮m thick) were then cut and stained with hematoxylin
and eosin and elastica van Giesson stains. For immunostains,
sections were incubated with rat monoclonal anti-mouse Mac-3
antibody (dilution 1:25; BD Biosciences), mouse monoclonal anti–
␣-SMA, and rabbit polyclonal anti-HDC antibody.
Reverse Transcriptase–Polymerase Chain Reaction
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Total RNAs extracted from mouse ligated carotid artery with Trizol
reagent (GIBCO/BRL) were subjected to RT-PCR for the GM-CSF
(448 bp), HDC (310 bp), HH1R (498 bp), and HH2R (601 bp) genes.
Primers used were as follows: GM-CSF (GenBank No. X03019),
5⬘-GGTCCTGAGGAGGATGTGG-3⬘/5⬘-TGGGCTTCCTCATTTTTGG-3⬘; HDC (GenBank No. X75437), 5⬘-GATCAGATTTCTACCTGTGG-3⬘/5⬘-GTGTACCATCATCCACTTGG-3⬘; HH1R
(GenBank No. D50095), 5⬘-TGCTTCAGCTACCATCCTGG-3⬘/5⬘GTCTGCATGACGTCAAGACG-3⬘; and HH2R (GenBank No.
D50096), 5⬘-AAGTCACCATCAGTGTGGTCC-3⬘/5⬘-ATGTGGTTGATCCTCTTGGC-3⬘. For HDC gene expression, quantitative
real-time PCR was performed by the TaqMan fluorogenic probe
method (Applied Biosystems).
Cell Culture
Human monocytic U937 cells (American Type Culture Collection)
were maintained in RPMI medium 1640 (GIBCO/BRL) containing
5% FCS (ICN).
Histamine Secretion From U937 Cells
U937 cells (5⫻105 per well) were stimulated with 10 or 20 ng/mL of
GM-CSF (PeproTech) for 72 hours. The conditioned medium was
then subjected to ELISA using a kit for histamine purchased from
SPI Bio according to manufacturer instructions.
Western Blotting for HDC Expressed in
U937 Cells
U937 cells were treated with 10, 20, or 50 ng/mL GM-CSF or 20
ng/mL phorbol 12-myristate 13-acetate (PMA; Sigma) for 24 hours.
Cells were lysed in a buffer (50 mmol/L Tris-HCl, pH 7.6,
120 mmol/L NaCl, 100 mmol/L NaF, 0.5% NP-40, and 10 ␮g/mL
phenylmethylsulfonyl fluoride), and the soluble fraction after centrifugation (⫻15 000g) was subjected to SDS-PAGE and Western
blotting. As a positive control, a lysate from rat mast cell line
RBL-2H3 was used.
Northern Blotting
U937 cells were stimulated with GM-CSF (10 or 20 ng/mL) for 24
hours. Total RNAs were extracted with Trizol reagent and electrophoresed on 1% agarose gel containing 6% formaldehyde. After
RNAs were transferred onto a nylon membrane, expression of HDC,
HH1R, and HH2R was detected by hybridization with 32P-labeled
probes.1,15 Equal loading of RNAs for each sample was confirmed by
methylene blue (0.02% in 0.5 mol/L sodium acetate, pH 5.2) staining
of the membrane to visualize 28S ribosomal RNAs.
Luciferase Reporter Assay
Reporter plasmids (pGL3-basic; Stratagene) containing the promoter
region of HDC,1 HH1R,16 and HH2R17 were used for the assay.
U937 cells (1.4⫻107/0.5 mL per cuvette) were transfected with 20
Figure 1. Immunolocalization of HDC in human atherosclerotic
carotid artery. A, Scanning view of a type VI lesion. F indicates
foam cells; L, lipid core; T, thrombi (hematoxylin and eosin). B,
At the shoulder of the lipid core, macrophages are positive for
HDC. C, The HDC-expressing macrophages were positive for
CD68 (D) but not for ␣-SMA.
␮g of reporter constructs along with 0.5 ␮g of ␤-galactosidase
(␤-gal) expression vector by electroporation (950 ␮F; 300 V GenePulser II, Bio-Rad). Cells were plated into 6 wells of a 24-well plate
and incubated with appropriate reagents for the desired periods. Cells
were lysed, and the supernatants were mixed with luciferase substrate (Toyo Ink). For cotransfection studies, pSG6 – c-Jun and
pSG6 – c-Fos18 were used (1 ␮g per cuvette). The dominant-negative
c-Jun (dKR)-19 expressing vector was generated using a site-directed
mutagenesis kit (Stratagene).
Statistical Analysis
Student t test was applied, and differences at P⬍0.05 were considered significant.
Results
Localization of HDC in Advanced Atherosclerotic
Lesion of Human Carotid Artery
We investigated carotid arteries showing advanced atherosclerosis, including accumulation of extracellular lipid and
complicated by thrombus and hematoma (type IV, V, and VI
lesions), in which macrophages were concentrated at the
lateral margins of the lipid core (Figure 1A). The macrophages facing the lipid core or the shoulder region were
positive for HDC (Figure 1B). In the complicating lesions
(type VI), macrophages located in the thrombus or hematoma
also expressed HDC (data not shown). The HDC-positive
macrophages were reactive with anti-CD68 antibody but not
with anti–␣-SMA (Figure 1C and 1D). Together with the
findings of the previous study showing the presence of
HDC-expressing macrophages in the fatty streaks (type II and
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Figure 2. Effect of GM-CSF on histamine production and HDC
gene expression in U937 cells. A, Effect of GM-CSF on histamine secretion from U937 monocytes. B, HDC protein expression in U937 cells. A dominant 54-kDa and minor 74-kDa bands
were detected. Note that GM-CSF increased the expression of
HDC in a dose-dependent manner. Extracts from PMA-treated
U937 cells and rat mast cells (RBL-2H3) include bands of the
same molecular weight. C, HDC gene expression in U937
monocytes (20 ␮g total RNA per lane). GM-CSF increased the
expression of HDC mRNA in a dose-dependent manner. mRNA/
28S ratio of HDC mRNA and 28S ribosomal RNA measured by
densitometry. Fold activation over the control mRNA/28S ratio
was calculated for each sample.
III lesions),1 these results indicate that histamine-producing
macrophages are present at all stages of atherosclerosis.
GM-CSF, HDC, and HHR Expression in Mouse
Ligated Artery
The ligated carotid arteries exhibited intimal thickening
where mainly SMCs were present. Macrophages were scattered in the intima but predominantly located on the endothelial surface and subendothelial space. These cells were
positive for the specific markers ␣-SMA and Mac-3, respectively. The distribution of Mac-3–positive macrophages corresponded to that of the HDC-expressing cells (Figure IA,
available online at http://atvb.ahajournals.org).
RT-PCR of material from the ligated arteries showed
enhanced expression of the GM-CSF, HH1R, and HH2R, and
HDC genes (Figure IB), indicating that the increased gene
expression is derived from the thickened intima. Because
intimal SMCs in culture express HH1R but not HH2R,6 the
expression of HH1R gene probably originated from SMCs,
ECs, and monocytes/macrophages. The expression of HH2R
gene might have been from ECs and monocytes/macrophages. GM-CSF expression has been demonstrated in
SMCs, ECs, and monocytes/macrophages.11 Thus, among
these cells, only monocytes/macrophages are suggested to
express the HDC and HHR genes.1,6
GM-CSF–Induced Histamine Production From
U937 Cells
GM-CSF increased histamine content in the medium (Figure
2A). Because the difference in cell numbers was ⬍10% in
each treatment, the increased histamine was suggested to
result from increased histamine secretion. Unlike mast cells,
monocytes do not have secretory granules, and their hista-
Figure 3. HDC promoter assay in U937 cells. A, Cells were
transfected with an HDC reporter plasmid and incubated with
GM-CSF for 8 hours. The transcriptional activity was enhanced
by GM-CSF in a dose-dependent manner. The activity was normalized by ␤-gal activity and expressed as fold activation over
the activity of a promoterless pGL3-basic vector (n⫽3 each). B,
dKR expression showed slight reduction of GM-CSF–induced
HDC promoter activity (*P⬍0.01; compare lanes 3 and 4). C,
c-Fos/c-Jun coexpression increased the basal activity, which
was further enhanced by GM-CSF (20 ng/mL; compare lanes 1
and 3). dKR repressed the c-Fos/c-Jun–mediated and GM-CSF–
induced promoter activation but still preserved the GM-CSF
response (lanes 2 and 4). B and C, Luciferase activity was normalized by ␤-gal activity and expressed as fold activation over
the activity of the wild-type HDC promoter without stimulation
(n⫽3 each).
mine secretion is mediated by transmembrane diffusion.
Therefore, histamine secretion from monocytes is mostly
dependent on histamine production, which is regulated by the
rate-limiting enzyme HDC. This was supported by the finding
that U937 cells stimulated with GM-CSF showed increased
expression of HDC protein in a dose-dependent manner
(Figure 2B). The dose-dependent expression of HDC mRNA
was confirmed by real-time quantitative RT-PCR (Figure II,
available online at http://atvb.ahajournals.org) and Northern
blotting (Figure 2C).
GM-CSF Transactivates HDC Gene Expression in
U937 Cells
The human HDC promoter region,1 spanning the region from
⫺240 to ⫹120 of transcription initiation site, includes gastrin
response element (GAS-RE) motif (⫹1 to ⫹27), a minimal
enhancer element(s) responsive to gastrin and PMA, which
contains the proximal GAS-RE1 and the distal GAS-RE2.20
GM-CSF increased HDC promoter activity in U937 cells
(Figure 3A), and the activity was reduced by introduction of
a mutation in the GAS-RE motif1 as well as reduction of the
Murata et al
GM-GSF Regulation of Histamine
433
basal activity (Figure III, available online at http://atvb.ahajournals.org). When U937 cells were transfected with M1
(GAS-RE1 mutation) and M2 (GAS-RE2 mutation), the basal
and GM-CSF–induced activity was significantly decreased,
indicating that the GAS-RE motif is essential for basal
activity and the response to GM-CSF.
Effects of Fos and Jun on HDC Gene Expression
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Expression of the HDC gene is regulated through GAS-RE
and indirectly via activation of the activator protein-1 (AP-1)
pathway in gastric cancer cells.21 In monocytic U937 cells,
GM-CSF is known to activate the c-Fos/c-Jun pathway and to
increase the expression of c-Jun during macrophage differentiation.22 To study the involvement of Fos/Jun in HDC gene
transcription, coexpression of c-Jun, c-Fos, and dKR was
introduced. dKR lacks the DNA-binding domain and can
dimerize with c-Jun and c-Fos but cannot transactivate.19
dKR showed no effect on the basal promoter activity
(Figure 3B, lanes 1 and 2) but exhibited a slight but
statistically significant (P⬍0.01) inhibitory effect on the
GM-CSF–induced activity (Figure 3B, lanes 3 and 4). When
c-Fos and c-Jun were coexpressed, basal activity was increased, and this upregulation was blocked by the combination of dKR and c-Fos (Figure 3C, lanes 1 and 2). With
stimulation by GM-CSF, the coexpression of c-Fos and dKR
showed reduced activity than that of c-Fos and c-Jun (Figure
3C, lanes 3 and 4). However, the response to GM-CSF was
still preserved even with the expression of dKR (Figure 3C,
compare lanes 2 and 4).
Effects of GM-CSF and Fos/Jun on HH1R
Expression in U937 Cells
Northern blotting analysis revealed that GM-CSF induced
expression of HH1R mRNA in a dose-dependent manner.
HH2R mRNA was constitutively expressed and not induced
by GM-CSF (Figure 4A). When U937 cells were treated with
GM-CSF, HH1R promoter activity was enhanced dose dependently. The basal promoter activity of HH2R gene was
higher than that of the HH1R gene but did not respond to
GM-CSF (Figure 4B). These results indicate that HH1R gene
expression is inducible by GM-CSF, but the HH2R gene is
expressed constitutively and is not responsive to GM-CSF.
When U937 cells were transfected with dKR alone, the
basal promoter was not reduced (Figure 5A, lanes 1 and 2),
but the GM-CSF–induced HH1R promoter activity was
downregulated (Figure 5A, lanes 3 and 4). Basal activity was
markedly upregulated by coexpression of c-Fos and c-Jun
(Figure 5B, lane 1), and GM-CSF increased the activity
further (Figure 5B, lane 3). When c-Jun was substituted by
dKR, basal activity was decreased (Figure 5B, lane 2), and
the GM-CSF induction was abolished (Figure 5B, lane 4).
These data indicate that the AP-1 pathway would be directly
involved in HH1R gene regulation.
Discussion
In addition to the promotion of macrophage differentiation,
GM-CSF regulates MMP expression,23 extracellular matrix
production,24 cell adhesion,25 and proliferation.12,26 Because
these events are related to the pathogenesis of inflammation,
Figure 4. HHR expression in U937 monocytes. A, Expression of
HH1R mRNA but not HH2R mRNA was increased by GM-CSF
in a dose-dependent manner. mRNA/28S ratio of HDC mRNA
and 28S ribosomal RNA measured by densitometry. Fold activation over the control mRNA/28S ratio was calculated for each
sample. B, Promoter assay of the HHR gene in U937 cells. Cells
were transfected with the reporter plasmid and incubated with
GM-CSF for 16 hours. The HH1R transcriptional activity was
increased, whereas HH2R activity was constitutively high and
not responsive to GM-CSF. Activity was normalized by ␤-gal
activity and expressed as fold activation over the activity of the
promoterless pGL3-basic vector (n⫽3 each).
GM-CSF, a proinflammatory cytokine, is thought to be a key
molecule involved atherogenesis.13,27 In human atherosclerotic lesions, GM-CSF is expressed in SMCs, ECs, and
monocytes/macrophages.11,13,28 In this study, we demonstrated that HDC was expressed in the macrophages (CD68 or
Mac-3–positive cells) located in human and mouse arteriosclerotic lesions. Furthermore, the GM-CSF gene was coexpressed with the HDC and HHR genes in mouse ligated
carotid arteries. These genes were also detected in human
atherosclerotic lesions (data not shown). In monocytic U937
cells, the coordinated expression of HDC and HH1R is
enhanced by GM-CSF. Although we demonstrated no direct
causal link between atherogenesis and GM-CSF–induced
upregulation of HDC and HH1R, these results suggest that
GM-CSF not only promotes macrophage differentiation but
also regulates histamine metabolism in the lesion. HDCexpressing macrophages might be a potential source of
histamine in atherosclerosis, especially contributing to
chronic effects of histamine.
Transcriptional regulation of the human HDC and HH1R
genes is not yet fully understood. In the present study, we
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February 2005
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Figure 5. Effect of Fos/Jun on HH1R promoter activity. A, dKR
reduced GM-CSF–induced HH1R promoter activity (lanes 3 and
4) but not the basal activity (lanes 1 and 2). B, c-Fos/c-Jun
coexpression markedly enhanced the HH1R transcriptional
activity (lane 1), and GM-CSF (20 ng/mL) increased activity further (lane 3). dKR downregulated the Fos/Jun–induced and GMCSF–induced promoter activity (lanes 2 and 4). Luciferase activity was normalized by ␤-gal activity and expressed as fold
activation over the activity of the wild-type HDC promoter without stimulation (n⫽3 each).
demonstrated the molecular mechanisms for HDC and HH1R
gene regulation by GM-CSF. In regulation of the HDC and
HH1R genes, the individual expression of dKR exhibited no
effect on the basal promoter activity (Figures 3B and 5A).
However, when c-Fos was coexpressed, dKR showed a
suppressive effect compared with c-Jun and c-Fos coexpression (Figures 3C and 5B). This indicated that the dKR might
have an inhibitory effect on basal activity when the AP-1
complex is expressed in a higher level. However, in HDC
gene regulation, dKR showed only slight inhibition of GMCSF–induced promoter activity (Figure 3B). Furthermore, the
coexpression of c-Fos and dKR failed to suppress the response to GM-CSF (Figure 3C). Therefore, these results
indicated that the dKR cannot inhibit GM-CSF–inducible
activity of HDC gene transcription. In contrast, GM-CSF–
induced HH1R gene transcriptional activities were markedly
reduced by dKR in either presence or absence of c-Fos
coexpression (Figure 5). HH1R gene transcription would be
directly regulated by the AP-1 complex, which may be related
to regulation of basal and GM-CSF–inducible activities. In
contrast, basal but not GM-CSF–inducible transcription of
HDC gene would be regulated by AP-1. The difference in
gene regulation may be partly explained by the different
promoter structures of the genes; no AP-1 motif has been
detected in the human HDC gene, but 5 potential AP-1 sites
exist in the HH1R gene.16,20
Aside from the present study, only a few reports have
described cytokine regulation of HH1R expression.
Interleukin-4 (IL-4) is able to upregulate HH1R mRNA in
synovial fibroblasts and ECs,29,30 whereas platelet-derived
growth factor (PDGF)-BB can enhance the expression of
HH1R mRNA in intimal SMCs.9 However, little is known
about the molecular mechanism(s) of gene regulation by IL-4
and PDGF-BB, or in monocytes. Although the signaling
pathway of GM-CSF in U937 cells is still controversial, it
may play an important role in the coordinated expression of
HDC and HH1R in monocytes during macrophage
differentiation.
The functions of histamine in atherosclerosis still are not
clarified. We reported previously that HH1R expression is
enhanced in SMCs in human atherosclerotic arteries.9 In the
present and previous studies,1 we showed that HDCexpressing macrophages (CD68 or Mac-3–positive cells)
were located in the atheromatous plaque and neointima of
human and mice arteries, respectively. Because histamine is
as potent as PDGF-BB in stimulating intimal SMCs to
proliferate, and also enhance MMP-1 expression,10 the localization of HDC-expressing cells in the neointima in arteriosclerotic lesions seems reasonable for explaining the proliferation and migration of medial SMCs on the basis of the
“response to injury” hypothesis.27 This is consistent with a
report that an HH1R blocker reduced the intimal thickening
by inhibiting intimal cell proliferation in mice with
photochemical-induced arteriosclerosis.31 However, recent
studies indicated that the neointimal SMCs are derived from
circulating progenitor cells provided by the bone marrow.32–34
Thus, the origin of neointimal SMCs is still debatable and
remains to be clarified.
In the case of monocytes, we found that HHR switching
from HH2R to HH1R during macrophage differentiation is
closely related to histamine-mediated gene expression.6,15
Histamine downregulates lipopolysaccharide-induced expression of tumor necrosis factor-␣ via HH2R in monocytes,
whereas it upregulates that via HH1R in macrophages.6 In
contrast, monocytic expression of lectin-like oxidized lowdensity lipoprotein receptor-1 (LOX-1) and monocyte chemoattractant protein-1 (MCP-1) is increased by HH2R activation. After macrophage differentiation, in which HH1R is
dominantly expressed, histamine cannot induce LOX-1 and
MCP-1.15,35 The effects of histamine on monocytes/macrophages would be dependent on the receptor profile. Here we
demonstrated that GM-CSF can upregulate HH1R expression. The coordinated expression of HDC and HH1R induced
by GM-CSF might contribute to histamine metabolism and
the expression of atherosclerosis-related genes in monocytes/
macrophages in an autocrine and paracrine manner.
In summary, our studies demonstrated that HDC and HHR
are expressed in arteriosclerotic lesion, and that GM-CSF
upregulates HDC and HH1R expression in monocytes. Together with our previous studies,1,6,9,10,15,35 these data indicate
that locally produced histamine in the neointima might
participate in the regulation of atherosclerosis-related genes
in monocytes and SMCs and in SMC proliferation.
Acknowledgments
This work was supported in part by a grant from the Smoking
Research Foundation, Tokyo, Japan (to A.T.).
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Downloaded from http://atvb.ahajournals.org/ by guest on June 18, 2017
Granulocyte Macrophage−Colony Stimulating Factor Increases the Expression of
Histamine and Histamine Receptors in Monocytes/Macrophages in Relation to
Arteriosclerosis
Yoshitaka Murata, Akihide Tanimoto, Ke-Yong Wang, Masato Tsutsui, Yasuyuki Sasaguri,
Filip De Corte and Hiroshi Matsushita
Arterioscler Thromb Vasc Biol. 2005;25:430-435; originally published online October 28, 2004;
doi: 10.1161/01.ATV.0000148705.13411.65
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272
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