Role of Transforming Growth Factor β Type Ii Receptor in Hepatic Fibrosis: Studies of Human Chronic Hepatitis C and Experimental Fibrosis in Rats

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Abstract
Transforming growth factor β (TGF–β) is an antiproliferative and profibrogenic cytokine that signals through a receptor consisting of type I and type II (TβRII) components. We have examined changes in the expression of TβRII during liver injury, correlating this with the antiproliferative and profibrogenic effects of TGF–β1. The experimental material consisted of biopsy samples of liver from patients with chronic hepatitis C and rats in which liver injury was induced by ligation of the common bile duct. Stellate cells were isolated from normal or injured rat liver and studied as fresh isolates. In the biopsy samples from patients, mRNAs for TGF–β1 and TβRII were measured using competitive reverse polymerase chain reaction (PCR). TGF–β1 mRNA was significantly increased in chronic hepatitis C relative to healthy controls (P = .03), while TβRII mRNA was significantly decreased (P = .001). In the rat model, 5 days after bile duct ligation during increased TGF–β expression, mRNA for TβRII in stellate cells was 40% of that in stellate cells from control livers. This coincided with increased expression of collagen I mRNA and proliferation of stellate cells. The reciprocal relationship between expression of TGF–β and the type II receptor suggest ligand–mediated receptor down–regulation. The decreased level of TβRII appears to be permissive for proliferation while supporting ongoing fibrogenesis. We conclude that modulation of this receptor may be critical to the progression of wound repair in liver.