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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 (10−6m), PGE2 (10−6m), and 17-phenyl-trinor-PGE2 (10−9m) in a time- and dose-dependent manner. PGE2 was less potent than 17-phenyl-trinor-PGE2 in stimulating hepatocyte mitogenesis. Sulprostone (10−6m) and 11-deoxy-PGE1 (10−6m) 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-α dose-dependently inhibited PGE2- and 17-phenyl-trinor-PGE2-induced hepatocyte mitogenesis. Treatment with the EP1 receptor agonists significantly increased the secretion of TGF-α, reaching a maximum within 5 min. The increase in TGF-α 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-α, which is dependent on the EP1 receptor/G-protein involved in PLC regulation/PLC/Ca2+ system. The locally secreted TGF-α, in turn, acts as a complete mitogen that stimulates the tyrosine kinase/MAPK pathway in these cells.

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