TYPE-I PROCOLLAGEN PRODUCTION AND CELL-PROLIFERATION IS MEDIATED BY TRANSFORMING GROWTH-FACTOR-BETA IN A MODEL OF HEPATIC-FIBROSIS

Fibrosis is a significant component of advanced chronic inflammatory L iver diseases and is caused by the accumulation of extracellular matri x, including type I procollagen. The mechanism by which fibrosis devel ops in liver tissue remains unknown. We tested the effects of transfor ming growth factor beta(1) (TGF-beta), a cytokine that alters cell dif ferentiation and proliferation, and bleomycin, a cytotoxic glycopeptid e antibiotic, on cultured isolated rat hepatocytes. TGF-beta (1 ng/ml) inhibited radiolabeled thymidine incorporation 39% at 24 h and 69% at 48 h. Inhibition of hepatocyte proliferation was dose dependent. Bleo mycin (1 mu g/ml) significantly inhibited radiolabeled thymidine incor poration at 48 h (44%). Neutralizing antibody to TGF-beta (TGF-beta-Ab ) attenuated the inhibition of proliferation by TGF-beta and bleomycin in a concentration-dependent manner. The addition of either TGF-beta or bleomycin increased immunostaining of type I procollagen in hepatoc ytes. The addition of TGF-beta-Ab alone increased cell proliferation, suggesting that neutralization of endogenous TGF-beta may attenuate th e inhibition of hepatocyte proliferation. These data suggest that the hepatocyte contains type I procollagen and, under some conditions, pro duces TGF-beta. We propose that procollagen production in rat hepatocy tes is induced by TGF-beta and may be related to endogenous production of this cytokine in response to cell injury. The cytotoxic effect of bleomycin is mediated by TGF-beta and inhibition of TGF-beta and bleom ycin with TGF-beta-Ab attenuates the additive effects of those compoun ds on isolated rat hepatocytes. These data provide a model of collagen expression in isolated rat hepatocytes.