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Prostaglandin E₂ (EP₁) Receptor Agonist-Induced DNA Synthesis and Proliferation in Primary Cultures of Adult Rat Hepatocytes: The Involvement of TGF-

Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Josai University, 1-1, Keyakidai, Sakado City 350-0295, Japan

Address all correspondence and requests for reprints to: Masahiko Ogihara, Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Josai University, 1-1, Keyakidai, Sakado City 350-0295, Japan. E-mail: ogiharam{at}josai.ac.jp

We investigated the effects of prostaglandin (EP) receptor subtype agonists on DNA synthesis and proliferation in primary cultures of adult rat hepatocytes to elucidate their mechanisms of action. Maintained in short-term cultures (i.e. 3.5 h) in a serum-free, defined medium, hepatocyte parenchymal cells underwent DNA synthesis and proliferation in the presence of sulprostone (10^-6 M), PGE₂ (10^-6 M), and 17-phenyl-trinor-PGE₂ (10^-9 M) in a time- and dose-dependent manner. PGE₂ was less potent than 17-phenyl-trinor-PGE₂ in stimulating hepatocyte mitogenesis. Sulprostone (10^-6 M) and 11-deoxy-PGE₁ (10^-6 M) showed weak and insignificant stimulation, respectively, for hepatocyte mitogenesis. These effects of PGE₂, 17-phenyl-trinor-PGE₂, and sulprostone were abolished by treatment with a specific EP₁ receptor antagonist, SC-51322, or the PLC inhibitor U-73122. The effects of these EP₁ receptor agonists were potentiated by ionomycin and blocked by verapamil. Hepatocyte mitogenesis was almost completely blocked by specific inhibitors of growth-related signal transducers, such as genistein, wortmannin, PD98059, and rapamycin. A monoclonal antibody against TGF- dose-dependently inhibited PGE₂- and 17-phenyl-trinor-PGE₂-induced hepatocyte mitogenesis. Treatment with the EP₁ receptor agonists significantly increased the secretion of TGF-, reaching a maximum within 5 min. The increase in TGF- secretion was blocked by SC-51322, U-73122, somatostatin, and verapamil and potentiated by ionomycin. These results indicate that the proliferative mechanisms of action of EP₁ receptor agonists are mediated through an increase in the autocrine secretion of TGF-, which is dependent on the EP₁ receptor/G-protein involved in PLC regulation/PLC/Ca²⁺ system. The locally secreted TGF-, in turn, acts as a complete mitogen that stimulates the tyrosine kinase/MAPK pathway in these cells.

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