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(American Journal of Pathology. 2000;157:1693-1701.)
© 2000 American Society for Investigative Pathology

Regular Articles

The Mitogenic Activity of Hepatocyte Growth Factor on Rat Hepatocytes Is Dependent upon Endogenous Transforming Growth Factor-

Tomoaki Tomiya^*, Itsuro Ogata^*, Miho Yamaoka, Mikio Yanase^*, Yukiko Inoue^* and Kenji Fujiwara

From the First Department of Internal Medicine,^*
Faculty of Medicine, University of Tokyo, Tokyo; and the Third Department of Internal Medicine,
Saitama Medical School, Saitama, Japan

Both transforming growth factor- (TGF-) and hepatocyte growth factor (HGF) induce DNA synthesis in hepatocytes in vitro and in vivo. Hepatic and circulating levels of HGF have been reported to increase before an increase in TGF- levels in several rat models of liver regeneration. In addition, serum TGF- levels increase after an increase in serum HGF levels in patients with either partial hepatectomy or acute hepatitis. In this study, we investigate the significance of TGF- in hepatocyte proliferation. TGF- contents and DNA synthesis in cultured rat hepatocytes increased 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- mRNA oligonucleotide. Furthermore, the addition of anti-TGF- rabbit IgG suppressed the increase in DNA synthesis. When the anti-TGF- antibody was administered to rats after partial hepatectomy, the number of mitotic hepatocytes was reduced in comparison to rats treated with normal rabbit IgG. These results were observed even though hepatic HGF levels were increased equally in rats given either anti-TGF- antibody or normal rabbit IgG. Our results suggest that HGF stimulates TGF- production in rat hepatocytes, and that the mitogenic activity of HGF depends on endogenous TGF- activity.

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