Regulation of hepatocyte growth factor production and liver regeneration

肝、肾、肺损伤后肝细胞生长因子（HGF）的生成明显增加。组织中升高的HGF可能具有触发剩余细胞增殖的功能。本研究考察了细胞因子和其他生理活性化合物对培养的人皮肤成纤维细胞生成HGF的影响。在细胞融合培养中加入环AMP （cAMP）升高剂和各种生长因子，可显著刺激HGF的产生。暴露于霍乱毒素或福斯克林的成纤维细胞最大HGF分泌量分别是未处理细胞的8倍和6倍。8-溴基cAMP、二丁基cAMP、前列腺素E_2和肾上腺素均显著促进HGF分泌。HGF mRNA水平在5和10 h时没有显著升高，但在添加这些化合物后15 h或更长时间内显著升高。在从4个个体分离的人皮肤成纤维细胞和MRC-5人胚胎肺成纤维细胞中，更多的人皮肤成纤维细胞表达和生成HGF，尽管它们之间的增加程度不同。在融合的人皮肤成纤维细胞中加入EGF、PDGF、bFGF、aFGF和tgf - α也能显著刺激HGF的产生和细胞的增殖。任何两种EGF、PDGF和bFGF的最佳剂量的所有组合几乎具有相加效应。添加生长因子后，HGF mRNA水平在9 h或更长时间内升高，至少到60 h。高剂量PMA预处理导致PKC下调，但不降低生长因子对HGF生成的影响，反而增强了它们的作用。因此，生长因子诱导HGF可能独立于PKC激活而发生。tgf - β和地塞米松抑制camp升高剂和生长因子诱导的HGF生成。这些结果表明，体内HGF的表达可能同时受到camp介导途径和生长因子的调节。少

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