Roles of prostaglandin production and mitogen-activated protein kinase activation in hepatocyte growth factor-mediated rat hepatocyte proliferation.

Hepatocyte growth factor (HGF) and epidermal growth factor (EGF)-stimulated DNA synthesis in primary cultured rat hepatocytes. HGF-induced DNA synthesis was concentration-dependently inhibited by a cyclooxygenase inhibitor, indomethacin. BW755C, a dual inhibitor for cyclooxygenase and lipoxygenase activities, also inhibited hepatocyte growth. Prostaglandin E1 (PGE1), PGE2, and PGF2 alpha induced DNA synthesis even at such a low concentration as 5 nmol/L and potentiated [3H]thymidine incorporation induced by HGF in an additive manner. HGF caused arachidonic acid (AA) release and eicosanoid production. These events were detectable within 10 minutes after stimulation and lasted for at least 60 minutes. Furthermore, two proteins with approximately 40 kd were tyrosine phosphorylated by HGF. These proteins were identified as p42/p44 mitogen-activated protein (MAP) kinases by anti-MAP kinase immunoblots, which were known to activate cytosolic phospholipase A2 (cPLA2), a key enzyme in AA release. Activation of MAP kinases was detectable within 5 minutes after stimulation with HGF and lasted for at least 60 minutes. EGF-mediated DNA synthesis was also inhibited by the above cyclooxygenase inhibitors. EGF caused AA release and tyrosine phosphorylation of MAP kinases. These results suggest that HGF as well as EGF causes AA release, probably through activation of cPLA2 mediated by MAP kinases, and that PGs, metabolites of AA, might play a pivotal role in hepatocyte proliferation in an autocrine mechanism.