Transforming growth factor β 1 (TGF-β 1 ) has been implicated as inhibitor of cell proliferation and a potent inducer of apoptosis in vitro and in vivo after the administration of high doses. To assess the role of endogenous TGF-β 1 , we quantitated the cytokine and its receptors in rat liver during regenerative and hyperplastic growth, regression by apoptosis, and in hepatocellular carcinoma (HCC). This was accomplished by Northern blot analysis and by RNase protection assay of the messenger RNA (mRNA) of TGF-β 1 and TGF-β receptors (TβR) types I to III and by an activity bioassay of the TGF-β proteins. Untreated rat livers were found to contain 15.6 ؎ 4.8 ng TGF-β 1 protein/g tissue; TGF-β 2 protein was not detected. To induce toxic cell death and subsequent regenerative DNA synthesis in the liver, rats were treated with a necrogenic dose of carbon tetrachloride (CCl 4 ). After 24 and 48 hours, there was an upregulation of TGF-β 1 (mRNA, up to tenfold; protein, about twofold) and of TβRs (mRNA: two-to fourfold); that indicates an overall enhanced production of and sensitivity to TGF-β 1 , which may serve to confine the regenerative response. Hyperplastic liver growth and regression of the hyperplasia were induced by treatment with cyproterone acetate (CPA) or nafenopin (NAF) followed by withdrawal; neither mRNAs of TGF-β 1 and TβR types I to III nor TGF-β 1 protein exhibited significant changes during the growth phase or during regression by apoptosis. We also studied neoplastic growth. HCC, obtained after long-term treatment with NAF, exhibited high rates of cell replication and apoptosis. The majority of lesions contained mRNA and protein of TGF-β 1 and mRNA of TβR types I to III at concentrations similar to those of the surrounding tissue. In conclusion, during liver regeneration there is a pronounced upregulation of expression of both TGF-β 1 and TβRs I to III, but not during mitogen-induced liver growth or regression. It appears that apoptosis is induced via altered local concentration of TGF-β 1 in a paracrine and/or autocrine way. By this mechanism the lethal effects of TGF-β 1 may be locally confined, and overshoots of apoptosis in the liver may be prevented. (HEPATOLOGY 1998;28:717-726.)
Abbreviations: TGF- 1 , transforming growth factor  1 ; TR, TGF-β receptors; mRNA, messenger RNA; CPA, cyproterone acetate; NAF, nafenopin; HCC, hepatocellular carcinoma.