Download PDF
Thromb Haemost 2002; 88(03): 524-532
DOI: 10.1055/s-0037-1613247
Review Article
Schattauer GmbH

15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Tissue Factor Expression in Human Macrophages and Endothelial Cells: Evidence for ERK1/2 Signaling Pathway Blockade

S. Eligini
1   E. Grossi Paoletti Center, Department of Pharmacological Sciences, University of Milan, Milan, Italy
,
C. Banfi
1   E. Grossi Paoletti Center, Department of Pharmacological Sciences, University of Milan, Milan, Italy
,
M. Brambilla
1   E. Grossi Paoletti Center, Department of Pharmacological Sciences, University of Milan, Milan, Italy
,
M. Camera
1   E. Grossi Paoletti Center, Department of Pharmacological Sciences, University of Milan, Milan, Italy
,
S. S. Barbieri
1   E. Grossi Paoletti Center, Department of Pharmacological Sciences, University of Milan, Milan, Italy
,
F. Poma
1   E. Grossi Paoletti Center, Department of Pharmacological Sciences, University of Milan, Milan, Italy
,
E. Tremoli
1   E. Grossi Paoletti Center, Department of Pharmacological Sciences, University of Milan, Milan, Italy
,
S. Colli
1   E. Grossi Paoletti Center, Department of Pharmacological Sciences, University of Milan, Milan, Italy
› Author Affiliations
Further Information

Publication History

Received 10 March 2002

Accepted after revision 04 June 2002

Publication Date:
08 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Basic and clinical evidence has provided insight into the molecular events that link inflammation and coagulation. Increased expression of tissue factor (TF) by circulating and vascular cells has been indicated as responsible for the thrombotic complications associated with acute and chronic inflammation. TF is indeed inducible in circulating and vascular cells by cytokines and bacterial lipopolysaccharide (LPS) and its expression triggers the coagulation. The cyclopentenone prostaglandins are naturally occurring prostaglandin D2 (PGD2) derivatives that comprises prostaglandin J2 (PGJ2) and its metabolites Δ12-PGJ2 and 15-deoxyΔ12, 14-prostaglandin J2 (15d-PGJ2). These compounds, detected in vivo in a later phase of the inflammatory response, are characterized by anti-inflammatory activity and participate to the resolution of inflammation. We have here investigated the effect of 15d-PGJ2 on TF expression in human macrophages and endothelial cells (HUVEC). Our results indicate that 15d-PGJ2 down-regulates LPSand TNFα-induced TF activity, protein and mRNA through inhibition of TF gene transcription. The effect of 15d-PGJ2 is targeted to the NF-κB/I-κB pathway and to the mitogen activated protein kinase ERK1/2. A role of PPARγ activation in TF inhibition by 15d-PGJ2 was excluded. We conclude that 15d-PGJ2 negatively affects TF expression in macrophages and endothelial cells through a PPARγ-independent mechanism. This down-regulation may be crucial to limit excessive blood clotting activation in immuno-inflammatory diseases.

Keywords

Cyclopentenone prostaglandins - tissue factor - inflammation - thrombosis - macrophages - endothelial cells
 

  • References

  • 1 Edgington TS, Mackman N, Brand K, Ruf W. The structural biology of expression and function of tissue factor. Thromb Haemost 1991; 66: 67-79.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Carson SD, Brozna JP. The role of tissue factor in the production of thrombin. Blood Coagul Fibrinolysis 1993; 04: 281-92.
    CrossrefPubMedGoogle Scholar
  • 3 Drake TA, Cheng J, Chang A, Taylor jr FB. Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal E. coli sepsis. Am J Pathol 1993; 142: 1458-70.
    PubMedGoogle Scholar
  • 4 Todoroki H, Nakamura S, Higure A, Okamoto K, Takeda S, Nagata N, Itoh H, Ohsato K. Neutrophils express tissue factor in a monkey model of sepsis. Surgery 2000; 127: 209-16.
    CrossrefPubMedGoogle Scholar
  • 5 Esmon CT. Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin?. Blood 2000; 1477: 1113-6.
    PubMedGoogle Scholar
  • 6 Creasey AA, Chang ACK, Feigen L, Wun TC, Taylor jr FB, Hinshaw LB. Tissue factor pathway inhibitor (TFPI) reduces mortality from E. coli septic shock. J Clin Invest 1993; 91: 2850-6.
    CrossrefPubMedGoogle Scholar
  • 7 Taylor FB, Chang AC, Peer G, Li A, Ezban M, Hedner U. Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and inteleukin6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli. Blood 1998; 91: 1609-15.
    PubMedGoogle Scholar
  • 8 Broze jr GJ. Tissue factor pathway of coagulation:factor VII, tissue factor, and tissue factor pathway inhibitor. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD. (eds) Haemostasis and Thrombosis. vol 2 third edition Singapore: Churchill Livingstone; 1994: 349.
    Google Scholar
  • 9 Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 115-26.
    CrossrefPubMedGoogle Scholar
  • 10 Hansson GK. Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 12: 1876-90.
    PubMedGoogle Scholar
  • 11 Plutzky J. Inflammatory pathways in atherosclerosis and acute coronary syndromes. Am J Cardiol 2001; 88: 10K-15K.
    PubMedGoogle Scholar
  • 12 Shah PK. Plaque disruption and thrombosis: potential role of inflammation and infection. Cardiol Rev 2000; 01: 31-9.
    PubMedGoogle Scholar
  • 13 Libby P, Simon DI. Inflammation and thrombosis: the clot thickens. Circulation 2001; 103: 1718-20.
    CrossrefPubMedGoogle Scholar
  • 14 Libby P. Atheroma: more than mush. Lancet 1996; 348: S4
    PubMedGoogle Scholar
  • 15 Tremoli E, Camera M, Toschi V, Colli S. Tissue factor in atherosclerosis. Atherosclerosis 1999; 144: 273-83.
    CrossrefPubMedGoogle Scholar
  • 16 Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby D. Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med 1999; 05: 698-701.
    CrossrefPubMedGoogle Scholar
  • 17 Ianaro A, Ialenti A, Maffia P, Pisano B, Di Rosa M. Role of cyclopentenone prostaglandins in rat carrageenin pleurisy. FEBS Lett 2001; 508: 61-6.
    CrossrefPubMedGoogle Scholar
  • 18 Fitzpatrick FA, Wynalda MA. Albumin-catalyzed metabolism of prostaglandin D2 . J Biol Chem 1983; 258: 11713-8.
    PubMedGoogle Scholar
  • 19 Jiang C, Ting AT, Seed B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 1999; 391: 82-6.
    PubMedGoogle Scholar
  • 20 Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 1998; 391: 79-82.
    CrossrefPubMedGoogle Scholar
  • 21 Nagoshi H, Uehara Y, Kanai F, Maeda S, Ogura T, Goto A, Toyo-oka T, Esumi H, Shimizu T, Omata M. Prostaglandin D2 inhibits inducible nitric oxide synthase expression in rat vascular smooth muscle cells. Circ Res 1998; 82: 204-9.
    CrossrefPubMedGoogle Scholar
  • 22 Petrova TV, Akama KT, Van Eldik LJ. Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Δ12, 14-prostaglandin J2 . Proc Natl Acad Sci USA 1999; 96: 4668-73.
    CrossrefPubMedGoogle Scholar
  • 23 Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang C-H, Sengchanthalangsy LL, Ghosh G, Glass CK. 15-deoxy-Δ12, 14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway. Proc Natl Acad Sci USA 2000; 97: 4844-9.
    CrossrefPubMedGoogle Scholar
  • 24 Mackman N. Regulation of the tissue factor gene. FASEB J 1995; 09: 883-9.
    CrossrefPubMedGoogle Scholar
  • 25 Verma I, Stevenson J, Schwarz E, Van Antwerp D, Miyamoto S. Rel/NFΔB/IΔB family: intimate tales of association and dissociation. Genes Dev 1995; 09: 2723-35.
    CrossrefPubMedGoogle Scholar
  • 26 Colli S, Lalli M, Risè P, Mussoni L, Eligini S, Galli C, Tremoli E. Increased thrombogenic potential of human monocyte-derived macrophages spontaneously transformed into foam cells. Thromb Haemost 1999; 81: 576-81.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Jaffe EA, Nachman RL, Becker CG, Minick CR. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 1973; 52: 2745-56.
    CrossrefPubMedGoogle Scholar
  • 28 Tremoli E, Camera M, Maderna P, Sironi L, Prati L, Colli S, Piovella F, Bernini F, Corsini A, Mussoni L. Increased synthesis of plasminogen activator inhibitor-1 by cultured human endothelial cells exposed to native and modified LDLs. Arterioscler Thromb 1993; 13: 338-46.
    CrossrefPubMedGoogle Scholar
  • 29 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-54.
    CrossrefPubMedGoogle Scholar
  • 30 Dignam JD, Lebovitz RM, Roeder RG. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acid Res 1983; 11: 1475-88.
    CrossrefPubMedGoogle Scholar
  • 31 Pierce J, Suelter CH. An evaluation of the Coomassie Brilliant Blue G-250 dye-binding method for quantitative protein determination. Anal Biochem 1977; 81: 478-80.
    CrossrefPubMedGoogle Scholar
  • 32 Eligini S, Colli S, Basso F, Sironi L, Tremoli E. Oxidized low density lipoprotein suppresses expression of inducible cyclooxygenase in human macrophages. Arterioscler Thromb Vasc Biol 1999; 19: 1719-25.
    CrossrefPubMedGoogle Scholar
  • 33 Bartha K, Brisson C, Archipoff G, de la Salle C, Lanza F, Cazenave JP, Beretz A. Thrombin regulates tissue factor and thrombomodulin mRNA levels and activities in human saphenous vein endothelial cells by distinct mechanisms. J Biol Chem 1993; 268: 421-9.
    PubMedGoogle Scholar
  • 34 Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages: A novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol 1997; 17: 265-72.
    CrossrefPubMedGoogle Scholar
  • 35 Sambrook T, Fritsch EF, Maniatis T. (Eds). Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor. 1989
    Google Scholar
  • 36 Vu-Dac N, Chopin-Delannoy S, Gervois P, Bonnelye E, Martin G, Fruchart J-C, Laudet V, Staels B. The nuclear receptors peroxisome proliferatoractivated receptor a and apolipoprotein A-I expression by fibrates. J Biol Chem 1998; 273: 25713-20.
    CrossrefPubMedGoogle Scholar
  • 37 Castrillo A, Diaz-Guerra MJM, Hortelano S, Martin-Sanz P, Bosca L. Inhibition of IκB kinase and IκB phosphorylation by 15-Deoxy-Δ12, 14-Prostaglandin J2 in activated murine macrophages. Mol Cell Biol 2000; 20: 1692-98.
    CrossrefPubMedGoogle Scholar
  • 38 Rossi A, Kaphai P, Natoli G, Takahashi T, Chen Y, Karin M, Santoro MG. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature 2000; 403: 103-8.
    CrossrefPubMedGoogle Scholar
  • 39 Cernuda-Morollon E, Pineda-Molina E, Canada FJ, Perez-Sala D. 15deoxy-Δ12, 14-prostaglandin J2 inhibition of NF-κB-DNA binding through covalent modification of the p50 subunit. J Biol Chem 2001; 276: 35530-6.
    CrossrefPubMedGoogle Scholar
  • 40 Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-deoxy-Δ12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ. Cell 1995; 83: 803-12.
    CrossrefPubMedGoogle Scholar
  • 41 Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation. Cell 1995; 83: 813-9.
    CrossrefPubMedGoogle Scholar
  • 42 Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPARγdependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 2001; 07: 48-52.
    CrossrefPubMedGoogle Scholar
  • 43 Han J, Hajjar DP, Tauras JM, Feng J, Gotto jr AM, Nicholson AC. Tansforming growth factor-β1 (TGFβ1) and TGFβ2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-γ. J Biol Chem 1999; 275: 1241-6.
    PubMedGoogle Scholar
  • 44 Crutchley DJ, Hirsch MJ. The stable prostacyclin analogue, Iloprost, and prostaglandin E1 inhibit monocyte procoagulant activity in vitro. Blood 1991; 78: 382-6.
    PubMedGoogle Scholar
  • 45 Ricote M, Huang JT, Welch JS, Glass CK. The peroxisome proliferatoractivated receptor γ (PPARγ) as a regulator of monocyte/macrophage function. J Leukoc Biol 1999; 66: 733-9.
    CrossrefPubMedGoogle Scholar
  • 46 Oeth P, Parry GCN, Mackman N. Regulation of the tissue factor gene in human monocytic cells: role of AP-1, NF-κB/Rel, and Sp1 proteins in uninduced and lipopolysaccharide-induced expression. Arterioscler Thromb Vasc Biol 1997; 17: 365-74.
    CrossrefPubMedGoogle Scholar
  • 47 Moll T, Czyz M, Holzmuller H, Hofer-Warbinek R, Wagner E, Winkler H, Bach FH, Hofer E. Regulation of the tissue factor promoter in endothelial cells. Binding of NF-κB-, AP-1-, and Sp1-like transcription factors. J Biol Chem 1995; 270: 3849-57.
    CrossrefPubMedGoogle Scholar
  • 48 Oeth P, Mackman N. Salicylates inhibit lipopolysaccharide-induced transcriptional activation of the tissue factor gene in human monocytic cells. Blood 1995; 86: 4144-52.
    PubMedGoogle Scholar
  • 49 Mackman N. Protease inhibitors block lipopolysaccharide induction of tissue factor gene expression in human monocytic cells by preventing activation of c-Rel/p65 heterodimers. J Biol Chem 1994; 269: 26363-7.
    PubMedGoogle Scholar
  • 50 Orthner CL, Rodgers GM, Fitzgerald LA. Pyrrolidine dithiocarbamate abrogates tissue factor (TF) expression by endothelial cells: evidence implicating nuclear factor-κB in TF induction by diverse agonists. Blood 1995; 86: 436-43.
    PubMedGoogle Scholar
  • 51 Marx N, Mackman N, Schonbeck U, Yilmaz N, Hombach V, Libby P, Plutzky J. PPARα activators inhibit tissue factor expression and activity in human monocytes. Circulation 2001; 103: 213-9.
    CrossrefPubMedGoogle Scholar
  • 52 Xie S, O’Reagan DJ, Kakkar VV, Scully MF. 15-Deoxy-Δ12, 14 PGJ2 induces procoagulant activity in cultured human endothelial cells. Thromb Haemost 2002; 87: 523-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Levonen A-L, Dickinson DA, Moellering DR, Mulcahy RT, Forman HJ, Darley-Usmar VM. Biphasic effect of 15-deoxy-Δ12, 14-prostaglandin J2 on glutathione induction and apoptosis in human endothelial cells. Arterioscler Thromb Vasc Biol 2001; 21: 1846-51.
    CrossrefPubMedGoogle Scholar
  • 54 Brisseau GF, Dackiw AP, Cheung PY, Christie N, Rotstein OD. Posttranscriptional regulation of macrophage tissue factor expression by antioxidants. Blood 1995; 85: 1025-35.
    PubMedGoogle Scholar
  • 55 Mechtcheriakova D, Schabbauer G, Lucerna M, Clauss M, De Martin R, Binder BR, Hofer E. Specificity, diversity, and convergence in VEGF and TNF-α signaling events leading to tissue factor up-regulation via EGR-1 in endothelial cells. Faseb J 2001; 15: 230-42.
    CrossrefPubMedGoogle Scholar
  • 56 Guha M, O’Connell MA, Pawlinski R, Hollis A, McGovern P, Yan S-F, Stem D, Mackman N. Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor α expression by inducing Elk-1 phosphorylation and Egr-1 expression. Blood 2001; 98: 1429-39.
    CrossrefPubMedGoogle Scholar
  • 57 Hortelano S, Castrillo A, Alvarez AM, Bosca L. Contribution of cyclopentenone prostaglandins to the resolution of inflammation through the potentiation of apoptosis in activated macrophages. J Immunol 2000; 165: 6525-31.
    CrossrefPubMedGoogle Scholar
  • 58 Kondo M, Oya-Ito T, Kumagai T, Osawa T, Uchida K. Cyclopentenone prostaglandins as potential inducers of intracellular oxidative stress. J Biol Chem 2001; 276: 12076-83.
    CrossrefPubMedGoogle Scholar
  • 59 Herschman HR, Reddy ST, Xie W. Function and regulation of prostaglandin synthase-2. Adv Exp Med Biol 1997; 407: 61-6.
    PubMedGoogle Scholar
  • 60 Offenbacher S, Odle BM, Van Dyke TE. The use of crevicular fluid prostaglandin E2 levels as a predictor of periodontal attachment loss. J Periodontal Res 1986; 21: 101-12.
    CrossrefPubMedGoogle Scholar
  • 61 Fukushima M. Prostaglandin J2 anti-tumour and anti-viral activities and the mechanisms involved. Eicosanoids 1990; 03: 189-99.
    PubMedGoogle Scholar
  • 62 Shibata T, Kondo M, Osawa T, Shibata N, Kobayashi M, Uchida K. 15-Deoxy-Δ12, 14-prostaglandin J2: A prostaglandin D2 metabolite generated during inflammatory processes. J Biol Chem 2002; 271: 10459-66.
    PubMedGoogle Scholar
  • 63 Ardissino D, Merlini PA, Bauer KA, Bramucci E, Ferrario M, Coppola R, Fetiveau R, Lucreziotti S, Rosenberg RD, Mannucci PM. Thrombogenic potential of human coronary atherosclerotic plaque. Blood 2001; 98: 2726-29.
    CrossrefPubMedGoogle Scholar
  • 64 Moreno PR, Palacios IF, Leon MN, Rhodes J, Fuster V, Fallon JT. Histopathologic comparison of human coronary in-stent and post-ballon angioplasty restenotic tissue. Am J Cardiol 1999; 84: 462-6.
    CrossrefPubMedGoogle Scholar
  • 65 Mizuno O, Ikeda U, Hojo Y, Fujikawa H, Katsuki T, Shimada K. Tissue factor expression in coronary circulation as a prognostic factor for late restenosis after coronary angioplasty. Cardiology 2001; 95: 84-9.
    CrossrefPubMedGoogle Scholar
  • 66 Banai S, Gertz SD. Tissue factor as a therapeutic target in coronary syndromes. Am J Cardiol 2001; 87: 763-5.
    CrossrefPubMedGoogle Scholar
  • 67 Cipollone F, Marini M, Iezzi A, Fazia M, Pini B, De Cesare D, Paloscia L, Materazzo G, D’Annunzio E, Cuccurullo F, Mezzetti A. Preprocedural low plasma level of 15-deoxy-Δ12, 14-prostaglandin J2 is associated with enhanced inflammatory response and restenosis after PTCA. Abs PPARs: from Basic Science to Clinical Applications, Florence, Italy, April. 2001
    PubMedGoogle Scholar