Regulation of hepatocyte growth factor production and liver regeneration

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Production of hepatocyte growth factor (HGF) markedly increases after injury of liver, kidney and lung. Elevated HGF in the tissues may have a function in triggering proliferation of the remaining cells. In this study, effects of cytokines and other physiologically active compounds on HGF production by human skin fibroblasts in culture were examined. Addition of cyclic AMP (cAMP) -elevating agents and various growth factors to confluent cultures of the cells markedly stimulated HGF production. The maximal secretion of HGF by the fibroblasts exposed to cholera toxin or forskolin was 8 or 6 times that by the untreated cells, respectively. 8-Bromo-cAMP,dibutyryl cAMP, prostaglandin E_2 and epinephrine also remarkably enhanced HGF secretion. HGF mRNA levels did not significantly increase at 5 and 10 h, but increased considerably 15 h or more after the addition of these compounds. Activation of the cAMP-mediated pathway by the cAMP-elevationg agents and the cAMP analogues enhanced HGF gene … More expression and HGF production in human skin fibroblasts isolated from four individuals and in MRC-5 human embryonic lung fibroblasts, although the extent of increase was variable among them. Addition of EGF, PDGF, bFGF, aFGF and TGF-alpha to confluent human skin fibroblasts also markedly stimulated HGF production as well as proliferation of the cells. All combinations of the optimal doses of any two EGF,PDGF and bFGF had nearly additive effects. The HGF mRNA levels were elevated at 9 h or more, at least until 60 h, after addition of the growth factors. Pretreatment with a high dose of PMA, which causes down-regulation in PKC,did not reduce the effects of the growth factors on HGF production, but rather enhanced them. Thus, induction of HGF by the growth factors may occur independently of PKC activation. TGF-beta1 and dexamethasone inhibited HGF production induced by the cAMP-elevating agents and the growth factors. These results suggest that HGF expression in vivo may be regulated by both a cAMP-mediated pathway and the growth factors. Less