© 2000 American Heart Association, Inc.
Vascular Biology |
Cyclooxygenase-2 Regulates Granulocyte-Macrophage Colony–Stimulating Factor, but Not Interleukin-8, Production by Human Vascular Cells
Role of cAMP
From the Unit of Critical Care (S.J.S., J.A.M.) and Department of Cardiothoracic Surgery (J.R.P.), The Royal Brompton and Harefield N.H.S. Trust, Imperial College School of Medicine, London, UK.
Correspondence to Dr J.A. Mitchell, Unit of Critical Care, The Royal Brompton and Harefield N.H.S. Trust, Imperial College School of Medicine, Sydney Street, London SW3 6NP, UK. E-mail j.a.mitchell{at}ic.ac.uk
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Abstract |
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Abstract—Vascular smooth muscle is now recognized as an important site of mediator generation under inflammatory conditions. Indeed, the release of leukocyte activators, such as granulocyte-macrophage colony–stimulating factor (GM-CSF) and interleukin (IL)-8, by human arterial smooth muscle cells has recently been demonstrated. However, the potential for venous cells to release GM-CSF has not been addressed. We have shown that human vascular smooth muscle cells express the "inflammatory" form of cyclooxygenase (COX), cyclooxygenase-2 (COX-2), when stimulated with cytokines. In some nonvascular cell types, the COX activity has been shown to regulate the release of GM-CSF and IL-8, although the nature of the isoform responsible was not addressed. We show that human venous smooth muscle cells, like their arterial counterparts, release GM-CSF after stimulation with IL-1ß. Similarly, both cell types released IL-8. Under the same conditions, we found that COX-2 activity suppressed GM-CSF, but not IL-8, release by both types of human vascular cells. Moreover, the prostacyclin mimetic, cicaprost, and the cAMP analogue, dibutyryl cAMP, inhibited GM-CSF release from these cells. These observations suggest that COX-2 activity suppresses GM-CSF release via a cAMP-dependent pathway in human vascular cells and illustrates a novel mechanism by which this enzyme can modulate immune and inflammatory events.
Key Words: inflammation • neutrophils • aspirin • interleukin-8 • atherosclerosis
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Introduction |
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In healthy blood vessels, the luminal surface is lined by a continuous monolayer of endothelial cells. The vascular endothelium, by expression of surface molecules and release of biologically active mediators, regulates vascular tone and function. In vascular diseases, such as atherosclerosis and septic shock, damage to the vessel wall results in endothelial cell disruption. This leads to the recruitment and activation of inflammatory cells, at and within the vessel wall, exacerbating and propagating the inflammatory response. Neutrophils are the first inflammatory cells to appear at the site of vessel damage.
Interleukin (IL)-8 is a CXC chemokine produced by a variety of cell types, including endothelial cells, monocytes, and fibroblasts. It is a powerful and specific neutrophil chemoattractant1 and, for this reason, is likely to be important in the initiation and propagation of vascular disease. Once neutrophils are present at the site of inflammation, they do not differentiate and rapidly die. Granulocyte-macrophage colony–stimulating factor (GM-CSF), released from a wide range of cells, is one of a number of colony-stimulating factors responsible for the proliferation and differentiation of cells in the bone marrow.2 This cytokine also modulates the function of circulating mature leukocytes, including neutrophils. GM-CSF promotes activation, surface receptor expression, and survival of mature neutrophils3 and, therefore, may be implicated, like IL-8, in the pathogenesis of vascular disease and also have an established role as an immunomodulator.
Loss of or damage to the endothelium results in the
exposure of underlying smooth muscle cells. These cells
represent the major cell type in the media of normal human
arteries and veins and, therefore, are potentially an important source
of inflammatory mediators. Their ability to release such mediators,
under inflammatory conditions, is currently the subject of
investigation. Indeed, we have recently demonstrated the expression of
the inducible inflammatory form of cyclooxygenase
(COX), cyclooxygenase-2 (COX-2), in and the
subsequent release of prostaglandins from the smooth muscle
component of human vessels stimulated in vitro with inflammatory
cytokines.4 5 Similarly, we have demonstrated that
the expression of COX-2 in human cultured venous and
arterial smooth muscle cells6 is under the
control of IL-1ß and tumor necrosis factor (TNF)-
. As well as
stimulating the expression of COX-2, these inflammatory
cytokines can also induce the release of IL-8 from human
cultured vascular smooth muscle cells7 and GM-CSF from
human cultured vascular8 and airway9 smooth
muscle. Therefore, our aim was to use human vascular smooth muscle
cells cultured from saphenous vein (SV) and internal mammary artery to
investigate the relative abilities of arterial and venous
cells to release IL-8 and GM-CSF. Furthermore, we have investigated the
effect of coinduced COX-2 on the release of these 2
cytokines.
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Methods |
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Materials
Human recombinant IL-1ß, TNF-
, and interferon-
(IFN-)
were bought from R & D Systems, and lipopolysaccharide (LPS)
was obtained from Sigma Chemical Co. Tritiated
prostaglandin (PG) E2 was purchased
from Amersham. Matched ELISA reagents to develop immunoassays for human
GM-CSF were bought from Pharmingen. Matched IL-8 antibody pairs and
human recombinant IL-8 required for human IL-8 ELISA were bought from R
& D Systems. For cell culture, Hanks’ balanced salt solution (HBSS)
and DMEM were purchased from Sigma, and MEM nonessential amino acids
were obtained from GIBCO-BRL. L-745,337 was a gift from Merck,
Harlow, UK and cicaprost was a gift from Dr F. McDonald at Schering,
Berlin, Germany. Nimesulide was from Sigma, and meloxicam was from
Boehringer-Ingelheim. All other reagents were from
Sigma.
Patients
Samples of internal mammary artery and SV, surplus to clinical
requirements, were obtained from patients undergoing coronary
artery bypass surgery at the Royal Brompton and Harefield N.H.S. Trust.
Vessels were used regardless of patient history and preoperative drug
therapy. Ethical permission was obtained from the Royal Brompton and
Harefield N.H.S. Trust ethics committee. In total, SV was obtained from
8 different patients, and internal mammary artery was obtained from
7 patients.
Statistics
All data are given as mean±SEM. Statistical significance was
calculated by 2-way ANOVA, 1-way ANOVA (Dunnett post hoc test), or
1-sample t test. A value of P<0.05 was taken
as significant.
Cell Culture
Vessels received in sterile pots direct from surgery were
prepared immediately under sterile culture conditions. Vessels were
placed in Petri dishes containing sterile HBSS supplemented with
penicillin (100 U/mL), streptomycin (0.1 mg/mL),
L-glutamine (2.0x10-3 mol/L), and
amphotericin B (1.0 µg/mL). Vessels were dissected clear of
connective tissue during the course of repeated washings in
supplemented HBSS. The vessels were then dissected along their length,
and the endothelium was carefully scraped off with a
scalpel blade. Vessels were cut into small pieces and placed in a
75-cm2 cell culture flask with DMEM containing
sodium pyruvate (110 mg/L) and phenol red and supplemented with
penicillin, streptomycin, glutamine, amphotericin B, MEM nonessential
amino acids, and 20% FCS.
After an initial 7-day period to allow the tissue pieces to adhere to
the bottom of the flask, explants received new supplemented DMEM every
3 or 4 days. After 
14 days, smooth muscle cells were seen as they
began to grow out from the edges of the tissue. At this point, the
concentration of FCS in the supplemented DMEM was reduced from 20% to
10%. After a period of 6 to 10 weeks, cells were fully confluent.
Adherent tissue pieces were then removed, and cells were passaged with
trypsin in supplemented HBSS. All experiments were performed with cells
(passages 2 to 6 only) from 2 to 3 different patients. For use in
experiments, cells were plated onto 96-well plates. When the cells
reached confluence, the phenotype of cells was synchronized to
"contractile" by withdrawing serum for 24 hours before treatment
with inflammatory cytokines and drugs.
Cell Treatment
At the beginning of each experiment, new supplemented DMEM (10%
FCS) was added to the cells. Cells were stimulated for 24 hours with
increasing concentrations of IL-1ß (1.0 pg/mL to 10 ng/mL), TNF-
(10 pg/mL to 10 ng/mL), IFN- (1.0 to 100 ng/mL), and LPS (1.0 to 100
µg/mL). In some experiments, vascular cells were pretreated (5
minutes) with different NSAIDs, including indomethacin
(1x10-7 to 1x10-5
mol/L), aspirin (1x10-5 to
1x10-3 mol/L), nimesulide
(1x10-7 to 1x10-5
mol/L), meloxicam (1x10-7 to
1x10-5 mol/L), and L-745,337
(1x10-7 to 1x10-5
mol/L) before the addition of either DMEM alone or DMEM containing
IL-1ß (1 ng/mL) for 24 hours. A further set of experiments was
carried out in which cells were treated for 24 hours with increasing
concentrations of PGE2
(1x10-8 to 1x10-5
mol/L), the prostacyclin (PGI2) mimetic cicaprost
(1x10-7 to 1x10-10
mol/L), or dibutyryl cAMP (1x10-8 to
1x10-4 mol/L) in the presence or absence of
IL-1ß (1 ng/mL) with or without indomethacin
(1x10-5 mol/L).
IL-1ß, TNF-, IFN-, LPS, cicaprost, and dibutyryl cAMP were
dissolved in DMEM. PGE2 was initially dissolved
in ethanol with all subsequent dilutions in DMEM (0.1% ethanol, final
concentration on cells). Indomethacin, aspirin,
meloxicam, nimesulide, and L-745,337 were all dissolved initially in
dimethyl sulfoxide (DMSO) with all subsequent dilutions in DMEM
(final concentration on cells: aspirin 1% DMSO;
indomethacin, meloxicam, nimesulide, and L-745,337
0.1% DMSO). In the concentrations present, neither DMSO nor
ethanol affected the release of PGE2 and GM-CSF
or cell viability as assessed by mitochondrial-dependent reduction of
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide to
formazan.10
PGE2 was measured by radioimmunoassay with the use of commercially available tritiated PGE2 as previously described.10 GM-CSF and IL-8 were measured by ELISA established in-house from individual constituents according to the manufacturers’ recommendations.
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Results |
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Release of PGE2, GM-CSF, and IL-8 From Human Cultured Arterial and Venous Smooth Muscle Cells
Human arterial smooth muscle cells spontaneously released low levels of PGE2 (7.7±1.1 ng/mL, n=41), GM-CSF (50.0±15.2 pg/mL, n=48), and IL-8 (5.7±0.3 ng/mL, n=9) over a 24-hour period under control culture conditions. Venous smooth muscle cells also spontaneously released PGE2 (18.4±2.9 ng/mL, n=45) and IL-8 (9.9±1.6 ng/mL, n=24) under these conditions. However, levels of GM-CSF released by venous cells were so low as to be undetectable by the ELISA protocol used (ie, <15.6 pg/mL, n=78).
When arterial cells were stimulated for 24 hours with
either IL-1ß (1.0 pg/mL to 10 ng/mL) or TNF- (10 pg/mL to 10
ng/mL), a concentration-dependent increase in
PGE2, GM-CSF, and IL-8 release was observed
(Figure 1
). Similarly, when venous cells
were stimulated with IL-1ß, there was a concentration-dependent
increase in PGE2, GM-CSF, and IL-8 release
(Figure 2). However, although TNF-
stimulated increases in PGE2 and IL-8 release by
venous cells, no detectable increase in GM-CSF release was observed
(Figure 2b). Excluding release of GM-CSF from
arterial cells (Figure 1b), stimulation of cells
with IL-1ß increased PGE2, GM-CSF, and IL-8
release to a greater extent than was observed with the same
concentrations of TNF-. Neither IFN- nor LPS had any effect on
the release of PGE2 or GM-CSF from
arterial or venous smooth muscle cells (data not shown).
However, LPS, but not IFN-, increased IL-8 release from both cell
types (data not shown). Arterial cells released less
PGE2 and more GM-CSF than did venous cells,
basally and in the presence of inflammatory cytokines (Figures 1a, 1b, 2a, and 2b).
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Effect of NSAIDs on PGE2, GM-CSF, and IL-8 Release From
Human Cultured Arterial and Venous Smooth Muscle
Cells
Basal release of PGE2 from
arterial and venous cells was abolished by pretreatment
(5 minutes) with the COX inhibitor
indomethacin (1.0x10-5 mol/L;
data not shown). In venous cells, basal release of GM-CSF was
undetectable and remained undetectable in the presence of
indomethacin (1.0x10-5 mol/L).
In arterial cells, basal release of GM-CSF was potentiated
in the presence of indomethacin (8.6±3.5 [n=36]
versus 25.4±9.7 [n=24] pg/mL). Indomethacin had no
effect on basal release of IL-8 (data not shown).
Indomethacin (1.0x10-7 to
1.0x10-5 mol/L) caused a
concentration-dependent decrease in PGE2 together
with a concentration-dependent increase in GM-CSF release in venous
cells (Figure 3a and 3b, respectively)
and arterial cells (for GM-CSF release, basal versus
the maximum effect (E-max) seen 217.1±83.9 versus 1132.5±57.4
pg/mL; n=3) treated with IL-1ß (1 ng/mL). However, pretreatment of
arterial and venous cells with indomethacin
in the presence of IL-1ß or TNF- had no effect on IL-8 release
from either cell type (data not shown).
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Pretreatment of venous cells with increasing concentrations of aspirin,
nimesulide, meloxicam, and L-745,337 (Figure 4a, 4b, 4c, and 4d, respectively) in the
presence of IL-1ß (1 ng/mL), as with indomethacin,
produced a concentration-dependent inhibition of
PGE2 and potentiation of GM-CSF release.
Similarly, treatment of arterial cells with increasing
concentrations of these NSAIDs in the presence of IL-1ß (1 ng/mL)
inhibited PGE2 and potentiated GM-CSF release
(for GM-CSF release, basal versus E-max 217.1±83.9 versus 732.5±71.4
pg/mL [aspirin], 217.1±83.9 versus 709.6±39.4 pg/mL [nimesulide],
217.1±83.9 versus 807.4±57.7 pg/mL [meloxicam], and 217.1±83.9
versus 1263.3±21.0 pg/mL [L-745,337]; n=3). In arterial
or venous smooth muscle cells pretreated with
indomethacin, nimesulide, meloxicam, and L-745,337, an
inhibition of PGE2 of >70% was required before
a significant increase in GM-CSF release was observed. Furthermore, a
complete inhibition of PGE2 release was required
before GM-CSF release was maximal. However, in both cell types,
pretreatment with aspirin resulted in GM-CSF release being maximum
before PGE2 release was maximally inhibited
(Figure 4a).
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Effect of Cicaprost, PGE2, and Dibutyryl cAMP on GM-CSF
Release From Human Cultured Arterial and Venous Smooth
Muscle Cells Stimulated With IL-1ß and Indomethacin
In venous cells (Figure 5) and
arterial cells (data not shown), PGE2
(1x10-8 to 1x10-5
mol/L), cicaprost (1x10-7 to
1x10-10 mol/L), and dibutyryl cAMP
(1x10-8 to 1x10-4
mol/L) inhibited, in a concentration-dependent fashion, the increase in
GM-CSF release observed from cells stimulated with IL-1ß (1 ng/mL) in
the presence of indomethacin
(1x10-5 mol/L). It is worth noting that the
endogenous levels of PGE2
(9.1x10-8±2.8x10-8
mol/L [arterial] and
7.0x10-7±1.1x10-7
mol/L [venous]; see Figures 1a
and 2a, respectively) released
after 24 hours by both smooth muscle cell types stimulated with IL-1ß
were below those required exogenously (EC50
>1.0x10-6 mol/L PGE2,
Figure 5) to inhibit GM-CSF release. In venous cells (Figure 5) and arterial cells (EC90
1.0x10-8 mol/L cicaprost), the
PGI2 mimetic cicaprost was more potent than
PGE2 at inhibiting GM-CSF release. This suggests
that PGI2, which is also released by these cells
after stimulation by IL-1ß,11 could be the
endogenous COX-2 product that is limiting GM-CSF
production.
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Discussion |
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The "inflammatory response" is mediated by a number of distinct chemical messengers that achieve biological effects individually as well as in association with each other. PGE2 and other COX metabolites have been implicated with inflammation for decades.12 Indeed, PGE2 facilitates plasma exudation and pain. In many types of inflammatory response, there is a clear association with the presence of activated neutrophils, edema, and severity of tissue damage.13 14 15 16 Thus, the release of mediators that attract (eg, IL-8), activate, or increase the longevity (eg, GM-CSF) of neutrophils is likely to occur simultaneously with the release of PGE2. The inflammatory mediators, PGE2, GM-CSF, and IL-8, are thought to be primarily released by endothelial cells or leukocytes. However, in the present study, we show that human vascular smooth muscle cells release PGE2, GM-CSF, and IL-8 spontaneously. In addition, we show that when stimulated with cytokines, human vascular smooth muscle cells release exaggerated amounts of these mediators. After stimulation with IL-1ß, human venous smooth muscle cells released more PGE2 than did equivalently treated arterial cells. This confirms our previous observations6 11 that related similar findings to a differential expression of COX-2 in the 2 cell types. By contrast, in the present study, we found that GM-CSF release was greater in arterial than venous cells. No appreciable difference was seen in the ability of arterial and venous cells to form IL-8.
The apparent inverse relation seen between the release of
PGE2 and GM-CSF by arterial and
venous cells suggested to us that there might be interactions between
these 2 mediators. Indeed, when COX activity was inhibited by
indomethacin, there was a concomitant reduction in
PGE2 and increase in GM-CSF release. This
observation is in keeping with the findings of others, who used a human
lung fibroblast cell line stimulated with
cytokines17 or human synovial fibroblasts
stimulated with IL-1.18 However, regarding human
synovial fibroblasts, it has been reported that
indomethacin potentiated fibroblast IL-8 release; this
finding contrasts with our own observations that the release of IL-8
from arterial and venous cells is unaffected in the
presence of indomethacin. Our results suggest that in
human cultured arterial and venous smooth muscle cells, COX
products are involved in the mechanism of GM-CSF, but not IL-8,
release. It has been reported that indomethacin has
actions other than the inhibition of COX.19 20 21 Such
reports introduce the possibility that our results are due to a direct
action of indomethacin on GM-CSF synthesis. We have
addressed this issue by repeating our experiments with a range of other
NSAIDs substituted for indomethacin. In every case, the
same concentration-dependent decrease in PGE2
(and corresponding increase in GM-CSF) release was observed, thus
firmly establishing a role for COX in the mechanism of GM-CSF
release.
The findings that COX activity differentially regulates GM-CSF versus IL-8 production suggest important differences in the regulation of these 2 genes. COX-2 is an immediate-early gene that is normally expressed transiently,22 whereas GM-CSF and IL-8 are thought to be continuously elevated in some inflammatory states.23 Thus, it is tempting to speculate that COX activity limits the survival-promoting GM-CSF until neutrophils are present, which are recruited by means of IL-8 production at the site of inflammation. Once present, COX activity may subside, resulting in a late burst of GM-CSF, which would be suitably timed for maximum impact in prolonging the survival of neutrophils.
Two isoforms of COX exist, COX-1 and COX-2.22 COX-1 is the constitutive form of the enzyme. COX-2, induced by inflammatory stimuli,24 25 is the predominant isoform present at sites of inflammation. In the present study, we find that in arterial and venous cells, the selective COX-2 inhibitor L-745,337,26 like all the NSAIDs tested, produces a concentration-dependent decrease in PGE2 release and an increase in GM-CSF release. This suggests that COX-2 products are modulating GM-CSF release in the present study. Our observations shed new light on previous studies showing that the COX-1/COX-2 inhibitor indomethacin increases GM-CSF release by human fibroblasts17 18 and suggest that in those studies, COX-2 was the isoform responsible for the apparent break in GM-CSF production.
In general, COX-1 and COX-2 perform the same enzymatic processes,
forming PGG2 and PGH2. The
profile of prostanoids produced by cells expressing either COX-1 or
COX-2 is therefore dependent on the distribution of "downstream"
synthase enzymes (eg, PGI2 synthase or
thromboxane synthase) or the oxidative state of the cells.
We have previously shown that when human venous or arterial
cells are stimulated to express COX-2, they synthesis
PGI2 and PGE2
predominantly, with very low levels of
thromboxane.11 Thus, it is likely that
PGI2 or PGE2 formed after
COX-2 induction is suppressing GM-CSF release in human venous or
arterial cells. Indeed, we found that either the
PGI2 mimetic cicaprost27 28 or
PGE2 was able to fully reverse the increase in
GM-CSF release produced by indomethacin in
cytokine-stimulated cells. The inhibitory action of
PGE2 on GM-CSF mRNA and protein levels in human
synovial fibroblasts,18 bone marrow stromal
cells,29 and WI-38 lung fibroblasts17 has
recently been reported. However, in human vascular cells, we found that
cicaprost was 10 000-fold more potent than
PGE2. Furthermore, the endogenous
levels of PGE2 released by both by smooth muscle
cell types stimulated with IL-1ß were below those required
exogenously to inhibit GM-CSF release, suggesting the involvement of
PGI2 receptors in this response.
Many of the biological effects of PGI2 are mediated by the second messenger, cAMP.30 31 Indeed, PGI2 receptors are linked to adenylyl cyclase, the activation of which leads to elevated levels of cAMP. In the present study, we observed that the cell-permeable cAMP analogue, dibutyryl cAMP, similar to cicaprost, inhibited the effects of indomethacin on GM-CSF release from cells stimulated with IL-1ß. These observations are in keeping with others recently published showing that dibutyryl cAMP inhibits GM-CSF expression in human bone marrow stromal cells29 and lung fibroblasts.17
PGI2 is a vasodilator with potent inhibitory actions on platelet function.32 33 34 Infusions of PGI2 or PGI2 mimetics are used therapeutically in the management of primary pulmonary hypertension and peripheral vascular disease and as an alternative to heparin infusion in hemofiltration. It has also been reported that PGI2 has antilipidemic properties35 and antimitotic actions on vascular smooth muscle cells36 and, thus, may be useful in the prevention/treatment of atherosclerosis. HDLs, the low plasma levels of which are indicative of atherogenesis, have been shown to increase COX-2 expression, inducing PGI2, in cytokine-stimulated endothelial cells.37 In many vascular diseases, including atherosclerosis, damage to the vessel wall leads to the recruitment and activation of inflammatory cells. Neutrophils are the first inflammatory cells to appear at the site of vessel damage, exacerbating and propagating the inflammatory response. It has also been reported that neutrophils generate reactive oxygen species, which may cause lipoprotein lipid oxidation, thereby contributing to the pathogenesis of atherosclerosis.38 39 40 Thus, we suggest that some of the anti-inflammatory/cytoprotective actions of PGI2 occur by inhibiting neutrophil survival as a direct consequence of reducing GM-CSF release at the site of inflammation.
In conclusion, we have shown that human vascular smooth muscle cells are a rich source of IL-8, GM-CSF, and COX-2 products. Moreover, we have identified and characterized an inhibitory pathway by which COX-2 activity suppresses GM-CSF (but not IL-8) release. Because GM-CSF promotes activation, surface receptor expression, and the survival of circulating mature neutrophils,3 these observations may help to explain some of the side effects associated with NSAIDs that are in current use. Moreover, we suggest that COX-2 inhibitors will also increase GM-CSF release under certain circumstances, an effect that may lead to side effects with these drugs. Our findings that cicaprost potently inhibits GM-CSF release may help to explain the mechanism of cytoprotection associated with PGI2 vascular diseases, such as pulmonary hypertension and peripheral vascular disease, in which neutrophil activation contributes to the disease.
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Acknowledgments |
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This study was funded by the British Heart Foundation and The Wellcome Trust. The authors wish to thank Prof T.W. Evans and Dr M. Belvisi for helpful discussion.
Received July 1, 1999; accepted October 13, 1999.
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References |
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