LEVELS OF TRANSFORMING-GROWTH-FACTOR-BETA AND TRANSFORMING-GROWTH-FACTOR-BETA RECEPTORS IN RAT-LIVER DURING GROWTH, REGRESSION BY APOPTOSISAND NEOPLASIA

Transforming growth factor beta(1) (TGF-beta(1)) has been implicated a s inhibitor of cell proliferation and a potent inducer of apoptosis in vitro and in vivo after the administration of high doses. To assess t he role of endogenous TGF-beta(1), we quantitated the cytokine and its receptors in rat liver during regenerative and hyperplastic growth, r egression by apoptosis, and in hepatocellular carcinoma (HCC). This wa s accomplished by Northern blot analysis and by RNase protection assay of the messenger RNA (mRNA) of TGF-beta(1) and TGF-beta receptors (T beta R) types I to III and by an activity bioassay of the TGF-beta pro teins. Untreated rat livers were found to contain 15.6 +/- 4.8 ng TGF- beta(1) protein/g tissue; TGF-beta(2) protein was not detected. To ind uce toxic cell death and subsequent regenerative DNA synthesis in the liver, rats were treated with a necrogenic dose of carbon tetrachlorid e (CCl4). After 24 and 48 hours, there was an upregulation of TGF-beta (1) (mRNA, up to tenfold; protein, about twofold) and of T beta Rs (mR NA: two- to fourfold); that indicates an overall enhanced production o f and sensitivity to TGF-beta(1), which may serve to confine the regen erative response. Hyperplastic liver growth and regression of the hype rplasia were induced by treatment with cyproterone acetate (CPA) or na fenopin (NAF) followed by withdrawal; neither mRNAs of TGF-beta(1) and T beta R types I to III nor TGF-beta(1) protein exhibited significant changes during the growth phase or during regression by apoptosis, We also studied neoplastic growth. HCC, obtained after long-term treatme nt with NAE exhibited high rates of cell replication and apoptosis, Th e majority of lesions contained mRNA and protein of TGF-beta(1) and mR NA of T beta R types I to III at concentrations similar to those of th e surrounding tissue. In conclusion, during liver regeneration there i s a pronounced upregulation of expression of both TGF-beta(1), and TPR s I to III, but not during mitogen-induced liver growth or regression. It appears that apoptosis is induced via altered local concentration of TGF-beta(1) in a paracrine and/or autocrine way. By this mechanism the lethal effects of TGF-beta(1) may be locally confined, and oversho ots of apoptosis in the liver may be prevented.