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LIVER AND BILIARY TRACT

Thrombin inhibits migration of human hepatic myofibroblasts

¹Institut National de la Santé et de la Recherche Médicale, U-889, ²Institut Fédératif de Recherche 66, Université Victor Segalen Bordeaux 2, and ³Centre Hospitalier Universitaire de Bordeaux, Groupement des Spécialités Digestives, Bordeaux, France

Submitted 15 January 2007 ; accepted in final form 21 March 2007

Several lines of data recently pointed out a role of the serine proteinase thrombin in liver fibrogenesis, but its mechanism of action is unknown. The aim of this study was to evaluate the effect of thrombin on the migration of human liver myofibroblasts. We show here that thrombin inhibits both basal migration and platelet-derived growth factor (PDGF)-BB-induced migration of myofibroblasts. By using a thrombin antagonist, a protease-activated receptor (PAR)-1 mimetic peptide, and a PAR-1 antibody, we show that this effect is dependent on the catalytic activity of thrombin and on PAR-1 activation. Thrombin's effect on basal migration was dependent on cyclooxygenase 2 (COX-2) activation because it was blocked by the COX-2 inhibitors NS-398 and nimesulide, and pharmacological studies showed that it was relayed through prostaglandin E₂ and its EP₂ receptor. On the other hand, thrombin-induced inhibition of PDGF-BB-induced migration was not dependent on COX-2. We show that thrombin inhibits PDGF-induced Akt-1 phosphorylation. This effect was consecutive to inhibition of PDGF- receptor activation through active dephosphorylation. Thus thrombin, through two distinct mechanisms, inhibits both basal- and PDGF-BB-induced migration of human hepatic liver myofibroblasts. The fine tuning of myofibroblast migration may be one of the mechanisms used by thrombin to regulate liver fibrogenesis.

liver fibrosis; hepatic stellate cell; cyclooxygenase; protease-activated receptor; phosphatidylinositol 3-kinase

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