The mitogenic activity of hepatocyte growth factor on rat hepatocytes is dependent upon endogenous transforming growth factor-alpha

Both transforming growth factor-alpha (TGF-alpha) and hepatocyte growth fac tor (HGF) induce DNA synthesis in hepatocytes in vitro and in vivo. Hepatic and circulating levels of HGF have been reported to Increase before an inc rease in TGF-alpha levels in several rat models of liver regeneration. In a ddition, serum TGF-alpha levels increase after an increase in serum HGF lev els in patients with either partial hepatectomy or acute hepatitis, In this study, we investigate the significance of TGF-alpha in hepatocyte prolifer ation. TGF-alpha contents and DNA synthesis in cultured rat hepatocytes inc reased in response to HGF addition to the culture medium in a dose-related manner. These increases were suppressed by the addition of anti-sense TGF-a lpha mRNA oligonucleotide. Furthermore, the addition of anti-TGF-alpha rabb it IgG suppressed the increase in DNA synthesis. When the anti-TGF-alpha an tibody was administered to rats after partial, hepatectomy, the number of m itotic hepatocytes was reduced In comparison to rats treated with normal ra bbit IgG. These results were observed even though hepatic HGF levels were i ncreased equally in rats given either anti-TGF-alpha antibody or normal rab bit IgG. Our results suggest that HGF stimulates TGF-alpha production in ra t hepatocytes, and that the mitogenic activity of HGF depends on endogenous TGF-alpha activity.