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J Biol Chem ; 279(7): 5200-6, 2004 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-14623891

RESUMO

The serine proteinase inhibitor tissue factor pathway inhibitor-2 (TFPI-2) inhibits the tissue factor-factor VIIa complex and thereby impairs factor Xa and subsequently thrombin generation. Here we show that thrombin itself up-regulates TFPI-2 mRNA and protein expression in human liver myofibroblasts, a cell type shown to express high levels of TFPI-2 (Neaud, V., Hisaka, T., Monvoisin, A., Bedin, C., Balabaud, C., Foster, D. C., Desmoulière, A., Kisiel, W., and Rosenbaum, J. (2000) J. Biol. Chem. 275, 35565-35569). This effect required thrombin catalytic activity, as shown by its abolition with hirudin. Although the thrombin effect could be mimicked by agonists of both protease-activated receptor (PAR)-1 and PAR-4, it was largely blocked by a PAR-1 blocking antibody. Transactivation of the epidermal growth factor (EGF) receptor has been reported as a common event in thrombin signaling. However, thrombin did not detectably transactivate the EGF receptor in liver myofibroblasts, and blocking the EGF receptor did not affect TFPI-2 induction. On the other hand, thrombin increased the expression of cyclooxygenase-2 (COX-2) mRNA via a MAPK-dependent pathway, and a specific COX-2 inhibitor abolished the effect of thrombin on TFPI-2 expression. Thus, thrombin, through PAR-1 signaling, up-regulates the synthesis of TFPI-2 via a MAPK/COX-2-dependent pathway. The up-regulation of TFPI-2 expression by thrombin could in turn down-regulate thrombin generation and contribute to limit blood coagulation.


Assuntos
Receptores ErbB/metabolismo , Glicoproteínas/biossíntese , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Trombina/fisiologia , Regulação para Cima , Northern Blotting , Western Blotting , Catálise , Células Cultivadas , Ciclo-Oxigenase 2 , DNA Complementar/metabolismo , Regulação para Baixo , Inibidores Enzimáticos/farmacologia , Hirudinas/metabolismo , Humanos , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana , Fosforilação , RNA/metabolismo , RNA Mensageiro/metabolismo , Receptor PAR-1/metabolismo , Receptores de Trombina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Trombina/metabolismo , Fatores de Tempo , Ativação Transcricional
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