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Prepublished online as a Blood First Edition Paper on May 1, 2003; DOI 10.1182/blood-2002-11-3607. This Article Full Text (PDF) All Versions of this Article: 2002-11-3607v1 102/5/1693    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Takeya, H. Articles by Suzuki, K. Search for Related Content PubMed PubMed Citation Articles by Takeya, H. Articles by Suzuki, K. Social Bookmarking                   What's this? Submitted December 2, 2002 Accepted April 24, 2003 Synergistic effect of sphingosine 1-phosphate on thrombin-induced tissue factor expression in endothelial cells Hiroyuki Takeya*, Esteban C Gabazza, Shinya Aoki, Hikaru Ueno, and Koji Suzuki Department of Molecular Pathobiology, Mie University School of Medicine, Tsu, Mie, Japan; Department of Biochemistry and Molecular Pathophysiology, University of Occupational and Environmental Health, School of Medicine, Kitakyusyu, Fukuoka, Japan * Corresponding author; email: takeya{at}med.uoeh-u.ac.jp. Sphingosine 1-phosphate (S1P), a bioactive lipid, is produced and stored in platelets and released from activated platelets during blood coagulation activation. Thrombin, which is also generated during blood coagulation, has been shown to induce tissue factor (TF), the initiator of blood coagulation, in endothelial cells (ECs); however, the effect of S1P on this process is not evaluated. Here we demonstrated that, S1P strongly potentiated thrombin-induced TF expression in ECs and that S1P itself did not induce TF expression. Among signaling lipids, platelet-activating factor slightly enhanced thrombin-induced TF expression, other lipids including lysophosphatidic acid, lysophosphatidylcholine, sphingosine, and C2-ceramide exert no effect on TF expression. S1P enhanced TF expression at transcriptional level, possibly via promoting the activation of transcription factors NF-kB and Egr-1. Thrombin weakly and S1P strongly activated ERK1/2 MAP kinase, and in the presence of both stimulants, enhanced and sustained activation of this kinase was observed. The ERK1/2 specific inhibitor PD98059 significantly inhibited enhanced TF expression induced by both stimulants, but only weakly inhibited thrombin-induced TF expression, thus indicating the requirement of ERK1/2 pathway in synergistic induction of TF expression. In addition, we found that thrombin and S1P rapidly upregulated the expression of S1P receptors, EDG-1 and -3, thereby suggesting that the effect of S1P on TF expression and other EC functions may be enhanced by thrombin and S1P itself. The present data reveal the synergistic effect of S1P on thrombin-induced TF expression in ECs, which may promote further thrombin and S1P generation, thus propagating a positive feedback reaction. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. I. Borissoff, H. M.H. Spronk, S. Heeneman, and H. ten Cate Is thrombin a key player in the 'coagulation-atherogenesis' maze? Cardiovasc Res, June 1, 2009; 82(3): 392 - 403. [Abstract] [Full Text] [PDF] J. Ahamed, F. Niessen, T. Kurokawa, Y. K. Lee, G. Bhattacharjee, J. H. Morrissey, and W. 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