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(Circulation. 2001;103:207.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

PPAR Agonists Inhibit Tissue Factor Expression in Human Monocytes and Macrophages

Bernadette P. Neve, PhD; Delphine Corseaux, PhD; Giulia Chinetti, PhD; Christophe Zawadzki, BS; Jean-Charles Fruchart, PhD; Patrick Duriez, PhD; Bart Staels, PhD; Brigitte Jude, MD

From the Département d’Athérosclérose, U.325 INSERM, Institut Pasteur de Lille, and the Faculté de Pharmacie, Université de Lille II (B.P.N., G.C., J.-C.F., P.D., B.S.), and the Laboratoire d’ Hématologie, Hôpital Cardiologique (D.C., C.Z., B.J.), Lille, France. The first 2 authors contributed equally to this article.

Correspondence to Brigitte Jude, Laboratoire d’Hématologie, Hôpital Cardiologique, Boulevard du Professeur J. Leclercq, 59037 Lille CEDEX, France. E-mail b-jude{at}chru-lille.fr

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—Monocytic tissue factor (TF) expression may contribute to thrombogenicity associated with plaque rupture and may propagate thrombus formation at the site of vascular lesions. Induction of monocytic TF expression by endotoxin is mediated by the activation of transcription factors such as AP-1 and NF-B. Both these signaling pathways are modulated by peroxisome proliferator–activated receptor- (PPAR). Therefore, we have studied the effects of fibrates and other PPAR agonists on the expression of TF.

Methods and Results—We show that PPAR protein, like primary human monocytes, is also expressed in the human monocytic THP-1 cell line. Fenofibric acid, WY14643, and GW2331 inhibited TF mRNA upregulation after stimulation of THP-1 cells with lipopolysaccharide or interleukin-1ß. In primary human monocytes and macrophages, the lipopolysaccharide- or interleukin-1ß–mediated induction of TF activity was also inhibited by fenofibric acid, WY14643, or GW2331.

Conclusions—These data indicate that activation of PPAR results in the downregulation of the TF gene. Our results suggest a novel role for PPAR in the control of atherosclerotic plaque thrombogenicity through its effects on TF expression in monocytes and macrophages.

Key Words: tissue factor • lipopolysaccharide • receptors • monocytes • fibrates

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Tissue factor (TF), a membrane-anchored glycoprotein, plays an important role in promoting coagulation and thrombosis.¹ TF initiates blood coagulation by forming a complex with circulating factors VII and VIIa.² Although physiologically absent from all intravascular cells, TF can be induced in monocytes by external signals such as growth factors, inflammatory cytokines (interleukin [IL]-1ß and tumor necrosis factor [TNF]-), oxidized LDLs, and endotoxin.² Monocytic TF activity has been implicated in several diseases associated with inflammation.³ In particular, TF antigen and mRNA have been localized in atheromatous plaques.^{4 5} Both monocytes and macrophages are involved in the progression of atherosclerosis and in the pathogenesis of thrombosis.⁶ Monocytic TF expression may contribute to thrombogenicity associated with plaque rupture.⁷ Moreover, TF from monocytes present in peripheral blood may propagate thrombus formation at the site of a vascular lesion.⁸

Peroxisome proliferator–activated receptor- (PPAR) is a ligand-dependent transcription factor that, on heterodimerization with the retinoid X receptor, binds to specific peroxisome proliferator response elements (PPREs) in the promoter of target genes, thus regulating the transcription of these genes. Transcription of affected genes may also be modulated by PPAR via interference with other transcription factor pathways. Activation of PPAR negatively interferes with nuclear factor-B (NF-B), signal transducer and activator of transcription (STAT), and activator protein-1 (AP-1) pathways.^{9 10 11}

PPAR, which plays an important role in the metabolism of fatty acids, lipids, and lipoproteins, has also been implicated in interference with atherogenic and inflammatory processes. PPAR-deficient mice show a prolonged response to inflammatory stimuli.¹² PPAR has been shown to inhibit transcription of several inflammatory response genes, which also occur in atherosclerotic plaques. In human aortic smooth muscle cells, fibrates inhibit the IL-1ß–induced expression of cyclooxygenase (COX)-2 and IL-6 by inhibiting the NF-B and AP-1 signaling pathway.^{9 10} In human vascular endothelial cells, PPAR inhibits the thrombin-mediated activation of endothelin-1 via negative interference with the AP-1 signaling pathway.¹³ Moreover, PPAR activators prevent TNF-–induced VCAM-1 expression in human saphenous vein endothelial cells, partly via inhibition of the NF-B pathway.¹⁴ This PPAR action may lead to a decreased recruitment of monocytes to early atherosclerotic lesions. In addition, PPAR is present in primary human monocytes, and its expression increases on differentiation into macrophages.¹⁵ Furthermore, PPAR activators induce apoptosis of TNF-–activated macrophages,¹⁵ most likely by inhibiting the antiapoptotic NF-B pathway.¹⁶

Although the TF promoter does not contain a PPRE, it contains Sp1-, Egr-1–, AP-1–, and NF-B–responsive elements.¹⁷ Induction of monocytic TF expression by endotoxin is mediated by the interaction of transcription factors such as AP-1 and NF-B with its promoter.^{17 18 19} Because both these signaling pathways are modulated by PPAR, we hypothesized that PPAR may modulate TF expression in human monocytes and macrophages. In the present report, the effect of several PPAR agonists on the endotoxin- and IL-1ß–mediated induction of TF expression was studied. We demonstrate that PPAR is also expressed in human monocytic THP-1 cells and that LPS- and IL-1ß–induced TF expression in THP-1, primary human monocytes, and macrophages is downregulated by activation of PPAR.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Materials
Fenofibric acid was a kind gift from A. Edgar (Fournier, Daix, France). WY14643 came from Chemsyn, and GW2331 was a kind gift from T. Willson (GlaxoWellcome Inc, Durham, NC). Escherichia coli lipopolysaccharide (LPS) and all trans-retinoic acid (ATRA) were purchased from Sigma Chemical Co and IL-1ß from Peprotech.

THP-1 Culture
Suspensions of human monocytic leukemia THP-1 cells were maintained in RPMI 1640 medium containing 25 mmol/L HEPES buffer and 10% FCS. The cell suspensions were grown at 37°C in a humidified 5% CO₂ atmosphere. Suspensions were diluted 1:1 when they reached a concentration of 1.5x10⁶ cells/mL. Cells were incubated 1 hour before LPS stimulation with either 100 µmol/L fenofibric acid, 10 µmol/L WY14643, 0.5 µmol/L GW2331, or 0.5 µmol/L ATRA. After addition of 10 µg/mL LPS, cells were further incubated for 2 hours. Then 5 mL of cell suspension was centrifuged (15 seconds, 10 000g), washed with PBS, and used for further RNA extraction.

Isolation and Culture of Human Monocytes
Venous blood obtained from healthy donors was anticoagulated with EDTA, and mononuclear cells were isolated by gradient centrifugation (separation medium MSL, d=1.077±0.001, Eurobio), washed 2 times with PBS, and resuspended in RPMI 1640 (1x10⁶ cells/mL). Monocytes were isolated from lymphocytes by adherence (1 hour at 37°C in a humidified 5% CO₂ atmosphere) to 96-well microplates. In separate experiments, monocytes were differentiated by culturing for 12 days in the presence of 10% human serum at 37°C in a humidified 5% CO₂ atmosphere. Cells were either preincubated with 100 µmol/L fenofibric acid, 10 or 100 µmol/L WY14643, 1 µmol/L GW2331, or 1 µmol/L ATRA for 4 hours before a 16-hour stimulation with LPS (0.4 ng/mL) or IL-1ß (10 ng/mL) at 37°C in a humidified 5% CO₂ atmosphere. At the end of the incubation period, the medium was removed, and plates were washed with cold PBS and assayed for TF activity. All reagents and culture supplies used were free of endotoxin (chromogenic limulus amoebocyte lysate assay; sensitivity, 0.025 endotoxin units/mL).

TF mRNA Analysis
Total RNA was prepared from THP-1 cells by acid guanidinium thiocyanate–phenol-chloroform extraction.²⁰ Fifteen micrograms of RNA was separated by electrophoresis and transferred to nylon membranes. Northern blots were hybridized at 68°C with radiolabeled TF or 36B4¹⁵ cDNA probes in ExpressHyb according to the manufacturer’s instructions (Clontech Laboratories). For the TF probe, a 641-bp cDNA product identical to the probe reported in the literature²¹ was isolated after reverse transcription–polymerase chain reaction amplification of RNA from human monocytes (primers, 5'-CTAGAATTCTACAAATACTGTGGCAGCATA-3'and 5'-ACGGAATTCCCCTTTCTCCTGGCCC-3'). The fragment was cloned into a pBSKS vector and its identity verified by sequence analysis.

TF Activity Assay
TF activity was determined by a modified amidolytic assay.²² Briefly, cells were mixed with 0.25 mol/L CaCl₂ (50 µL) and prothrombin concentrate complex (Laboratoire de Fractionnement et des Biotechnologies) as a source of factor VII (50 µL, 3 IU/mL). After addition of 50 µL of the chromogenic substrate S2765 (Biogenic), the change in optical density at 405 nm was quantified with a microplate reader and converted to units of TF activity by being plotted log to log with readings from standard dilutions of tissue thromboplastin. Arbitrarily, 1 mL of thromboplastin was assigned a value of 1000 U/mL of TF activity.

Statistics
Statistically significant differences between groups were reported when P0.05 through an ANOVA test followed by a Bonferroni correction.

	Results

Top Abstract Introduction Methods Results Discussion References

 
To determine the conditions for studying the effects of PPAR activators, the LPS-mediated induction of TF expression was monitored in monocytic THP-1 cells. As in other studies,^{19 21 23} LPS increased TF mRNA expression in these cells several-fold. After 2 hours of incubation with LPS, both the 2.2- and 3.4-kb mRNA species of TF were observed (Figure 1A). The 3.4-kb transcript may contain intron-1 and is probably not translated to protein.²¹ The 2.2-kb TF mRNA transcript was transiently induced, with a maximum after 2 hours of LPS stimulation. After 3 hours of incubation with LPS, the 2.2-kb transcript level was already decreased.

View larger version (64K): [in this window] [in a new window]   Figure 1. Expression of TF and PPAR in THP-1 cells stimulated with endotoxin. Cell suspensions were incubated with 10 µg/mL LPS. After indicated time (A) or after 2 hours (B), cells were collected by centrifugation. Pellet was used for either TF mRNA (A, top) and control 36B4 mRNA (A, bottom) analysis or PPAR protein analysis (B). Immunolabeling of PPAR protein was performed as described by Chinetti et al.15

To examine whether specific effects of PPAR activators could be expected in THP-1 cells, we analyzed the expression of PPAR in these cells. Both PPAR mRNA (not shown) and protein (Figure 1B) were detected in control and LPS-stimulated THP-1 cells. LPS had no effect on the level of PPAR protein expression.

Because PPAR is expressed in THP-1 cells, we further examined the effects of several PPAR activators on TF mRNA expression. Incubation of THP-1 cells with PPAR activators 1 hour before LPS stimulation for 2 hours resulted in a decreased level of TF mRNA compared with cells incubated with only LPS (Figure 2A). The PPAR agonists fenofibric acid and WY14643 inhibited LPS-mediated induction of TF mRNA to 61% and 46%, respectively, of the mRNA levels of cells incubated with LPS alone (Figure 2A). Moreover, coincubation of THP-1 cells with LPS and the potent PPAR agonist GW2331 (EC₅₀, 50 nmol/L²⁴ ) decreased TF mRNA expression to 39% of the level of LPS-stimulated cells.

View larger version (26K): [in this window] [in a new window]   Figure 2. TF mRNA expression in LPS- or IL-1ß–stimulated THP-1 cells after incubation with PPAR agonists and ATRA. Cell suspen- sions were incubated either without any addition of compounds or with 100 µmol/L fenofibric acid (Fenofibr.), 10 µmol/L WY14643, 0.5 µmol/L GW2331, or 0.5 µmol/L ATRA 1 hour before stimulation with LPS or IL-1ß. Two hours thereafter, cell suspensions were centrifuged, and pellet was used for further RNA analysis. Typical Northern blot of RNA isolated from cells incubated with 10 µg/mL LPS (A) or 10 ng/mL IL-1ß (B) in presence of indicated compounds. Blots were hybridized with TF (top) or control 36B4 (bottom) probe. Bar graph represents quantification of TF/36B4 mRNA signals of 3 to 4 independent experiments. Bars are mean±SEM. *Significant difference vs control (P<0.05).

To verify the extent of the TF mRNA inhibition, we compared the effects of the PPAR activators with those of ATRA, a previously identified negative regulator of TF expression.²⁵ ATRA inhibited the LPS-mediated induction of TF expression in THP-1 cells to 21% of the control level.

To investigate whether PPAR activators could also inhibit TF mRNA induction by other inflammatory stimuli, we studied their effects on THP-1 cells stimulated with IL-1ß. Like LPS-induced TF mRNA expression, PPAR agonists and ATRA inhibited IL-1ß–induced TF expression (Figure 2B). Both WY14643 and GW2331 decreased TF mRNA levels to 63% and 48%, respectively, of levels in cells incubated with IL-1ß alone. ATRA diminished the mRNA level to 19% of the IL-1ß–stimulated control.

Next, we studied the influence of PPAR agonists on TF activity in primary human monocytes. Incubation of unstimulated monocytes with fenofibric acid, WY14643, GW2331, or ATRA did not influence basal TF activity (Figure 3A). Incubation of monocytes with LPS or IL-1ß resulted in a 10- and 5-fold increase of TF activity, respectively. Preincubation with different PPAR agonists significantly inhibited both the LPS- and IL-1ß–induced TF activity (Figure 3B and 3C). The TF activity in LPS-stimulated monocytes decreased to 67%, 57%, and 56% on preincubation with fenofibric acid, WY14643, or GW2331, respectively. In IL-1ß–stimulated monocytes, the TF expression after fenofibric acid, WY14643, or GW2331 preincubation was decreased to 72%, 60%, and 45%, respectively, compared with IL-1ß only. The inhibitory effects of PPAR agonists on TF activity levels at the doses used correlated well with their relative potency for PPAR activation (GW2331>WY14643>fenofibric acid). ATRA inhibited IL-1ß–induced TF activity to 33% of the activity in stimulated monocytes. ATRA had no detectable effect on LPS-induced TF activity when preincubated, however, analogous to the PPAR agonists, for 4 hours (Figure 3C). Preincubation with ATRA for 30 minutes followed by an incubation for 16 hours with LPS, however, resulted in a pronounced downregulation (to 11%) of TF activity compared with LPS incubation alone.

View larger version (35K): [in this window] [in a new window]   Figure 3. Effect of different PPAR agonists and ATRA on TF activity in unstimulated and LPS- or IL-1ß–stimulated human monocytes. Cells were incubated for 4 hours with either fenofibric acid (Fenofibr., 100 µmol/L), WY14643 (100 µmol/L), GW2331 (1 µmol/L), or ATRA (1 µmol/L) and then incubated without (A) or with LPS (0.4 ng/mL) (B, D) or IL-1ß (10 ng/mL) (C) for 16 hours. Bars are mean±SEM from 3 to 4 independent experiments. *Significant difference vs control (P<0.05). D, TF activity expressed in monocytes incubated with or without 0.4 ng/mL LPS for indicated periods of time with 1 µmol/L ATRA.

Finally, we studied the effects of PPAR agonists on TF activity in human monocyte–derived macrophages (Figure 4). Preincubation of differentiated macrophages with the PPAR agonists fenofibric acid, WY14643, and GW2331 resulted in an inhibition of LPS-stimulated TF activity to 78%, 35%, and 13%, respectively, of the activity in cells incubated with LPS alone (Figure 4). Like the effects in LPS-stimulated monocytes, only a 30-minute and not a 4-hour preincubation of the LPS-stimulated macrophages with ATRA decreased the TF activity level (12% of control).

View larger version (50K): [in this window] [in a new window]   Figure 4. Effect of PPAR activators and ATRA on TF activity in human macrophages stimulated with LPS. Primary human monocytes were differentiated for 12 days in presence of 10% human serum. Thereafter, cells were incubated in serum-free conditions with either fenofibric acid (Fenofibr., 100 µmol/L), WY14643 (10 µmol/L), GW2331 (1 µmol/L), or ATRA (1 µmol/L). After a 4-hour preincubation, 0.4 ng/mL LPS was added, and cells were incubated for another 16 hours before TF activity was measured. In parallel, cells were preincubated for 30 minutes with ATRA before 16-hour LPS stimulation.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Induction of monocytic TF expression is mediated by signaling pathways, which can be modulated by PPAR activation. In the present study, we determined whether incubation with PPAR agonists modulates TF expression in the human monocytic THP-1 cell line and in human monocytes and macrophages. It was previously demonstrated that PPAR is present in primary human monocytes.¹⁵ Here, we extend these observations by showing that PPAR protein is also expressed in THP-1 cells. Furthermore, our study demonstrates that PPAR activation can inhibit TF upregulation in THP-1 cells and in primary human monocytes and macrophages. Thus, these results extend previous observations identifying a role for PPAR in human monocytes and, moreover, for the first time point out a possible role for PPAR in the control of atherosclerotic plaque thrombogenicity.

The activity of PPAR agonists on the downregulation of TF expression was compared with that of ATRA. Retinoic acid has been shown to inhibit the LPS-induced TF expression in human THP-1 cells, monocytes, and macrophages.^{25 26 27} We confirmed these effects for LPS- and IL-1ß–induced TF mRNA expression in THP-1 cells. As previously demonstrated for macrophages,²⁶ the inhibitory effect of ATRA on LPS-stimulated TF activity in monocytes appeared to depend on the time of preincubation with retinoids. Whereas preincubation of monocytes with ATRA for 4 hours inhibited IL-1ß–induced TF activity, no inhibition of LPS-induced TF activity was observed. However, a limited preincubation of 30 minutes with ATRA completely prevented the LPS induction of TF activity in monocytes and macrophages. The bases for these apparent kinetic differences, as well as the mechanism by which ATRA inhibits the induction of TF mRNA expression, are poorly known.

PPAR may interfere with proatherogenic processes at different levels. First, PPAR exerts beneficial effects on atherosclerosis by changing plasma lipid and lipoprotein profiles toward less atherogenic levels. Second, PPAR interferes with the development of atherosclerosis by inhibiting inflammatory responses at the level of the vascular wall.^{9 10 12} PPAR may interfere with the early stages of atherosclerotic lesion development by affecting monocyte recruitment by inhibiting TNF-–induced VCAM-1 expression in endothelial cells.¹⁴ Furthermore, PPAR may also influence later stages of atherosclerosis by inducing apoptosis of activated human macrophages.¹⁵ Our results demonstrate that PPAR activation also inhibits TF expression, which is a major initiator of thrombosis. In addition, TF may mediate adhesion and migration of monocytes.²⁸ Thus, inhibition of monocytic TF expression is another way by which PPAR may modulate atherogenic processes.

We have shown that PPAR activators inhibit the expression of TF after induction by the inflammatory stimuli LPS and IL-1ß. Induction of TF mRNA by LPS has been shown to occur via Jun phosphorylation and NF-B translocation in a rapid but transient way.¹⁹ PPAR inhibits the proinflammatory AP-1 and NF-B signaling pathways by repression of both c-Jun and p65 transcription activity.^{9 10 13} Because these factors also control TF promoter transcription, it is likely that PPAR modulates TF expression also by interfering negatively with the AP-1 and/or NF-B activation pathway. Further molecular studies are necessary to determine whether the repression of TF gene expression by PPAR agonists indeed occurs via cross talk of PPAR with other transcription factors, such as Jun-Fos and NF-B.

In conclusion, the PPAR agonists fenofibric acid, WY14643, and GW2331 all inhibit the upregulation of TF expression, which occurs after stimulation of THP-1 cells or human monocytes with LPS or IL-1ß. The effect of PPAR stimulation on monocyte and macrophage TF expression suggests a novel role for PPAR in atherosclerosis by influencing atherosclerotic plaque thrombogenicity. In vivo studies using atherosclerotic animal models may elucidate whether PPAR is able to reduce the thrombogenicity of atherosclerotic plaques by lowering TF expression.

	Acknowledgments

 
This study was supported by grants from the Comité Français de Coordination des Recherches sur L’athérosclérose (ARCOL), Laboratoire Fournier, le Groupe de Reflexion sur la Recherche Cardiovasculaire, and Bristol Myers Squibb (to Dr Corseaux); the TMR Program of the European Community (FMBICT983400, to Dr Neve); the Fondation pour la Recherche Médicale (to Dr Chinetti); the European Community (QLRT-1999-01007, to Dr Chinetti); and the University of Lille II (EA2693, to Drs Corseaux and Jude and C. Zawadzki).

Received August 14, 2000; revision received September 26, 2000; accepted September 26, 2000.

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