Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: Potential role in liver injury

Fabio Marra, Giuseppe Grandaliano, Anthony J. Valente, Hanna E. Abboud

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Abstract

Liver fat-storing cells (FSC) proliferate and secrete extracellular matrix in experimental models of liver injury. In this study, we determined if thrombin, a serine protease produced during acute and chronic tissue injury, modulates the functions of FSC. Thrombin stimulated DNA synthesis and proliferation of FSC, as assessed by [3H]-thymidine incorporation assay and measurement of cell number, respectively. Thrombin also increased the secretion of monocyte chemotactic protein-1 (MCP-1) in a time- and dose-dependent fashion. The effect of thrombin on both DNA synthesis and MCP-1 secretion was neutralized by pretreatment of thrombin with hirudin. The increased MCP-1 secretion was associated with increased steady-state levels of MCP-1 messenger RNA. Pretreatment of FSC with 5 μmol/L retinol for 48 hours inhibited the mitogenic effects of thrombin but not the induction of MCP-1 secretion. FSC express specific transcripts encoding for the human thrombin receptor, as shown by Northern blot analysis of poly(A)+ RNA. Proteolytic activation of the thrombin receptor results in the formation of a new N-terminus that functions as a tethered ligand. We studied the effects of a thrombin receptor activating peptide (TRAP) corresponding to the newly formed N-terminus, on FSC. TRAP mimicked the effects of thrombin on [3H]-thymidine incorporation, MCP-1 secretion, and MCP-1 gene expression. This study suggests that thrombin may be involved in modulating FSC proliferation and monocyte chemotaxis during human liver disease, through proteolytic activation of its receptor.

Original languageEnglish (US)
Pages (from-to)780-787
Number of pages8
JournalHepatology
Volume22
Issue number3
DOIs
StatePublished - Sep 1995

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ASJC Scopus subject areas

  • Hepatology

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