Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: Potential role in liver injury
✍ Scribed by Dr Fabio Marra; Giuseppe Grandaliano; Anthony J. Valente; Hanna E. Abboud
- Publisher
- John Wiley and Sons
- Year
- 1995
- Tongue
- English
- Weight
- 844 KB
- Volume
- 22
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
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 ['HI-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 pmollL 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 Nterminus 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 ['HIthymidine 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.