Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury.
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 mumol/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 suggest that thrombin may be involved in modulating FSC proliferation and monocyte chemotaxis during human liver disease, through proteolytic activation of its receptor.
Marra
F
F
Department of Medicine, University of Texas Health Science Center at San Antonio 78284, USA.
Grandaliano
G
G
Valente
A J
AJ
Abboud
H E
HE
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2; D002630:Chemotactic Factors / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008107:Liver Diseases / Q000209:etiology*; D010446:Peptide Fragments / Q000494:pharmacology; D018179:Receptors, Thrombin / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology*; D014801:Vitamin A / Q000494:pharmacology
D018932:Chemokine CCL2; D002630:Chemotactic Factors; D016207:Cytokines; D010446:Peptide Fragments; D018179:Receptors, Thrombin; D014801:Vitamin A; C086309:thrombin receptor peptide SFLLRNP; D004247:DNA; D013917:Thrombin