The study on the stimulation of liver regeneration and recovery from liver injury by inducers of hepatocyte growth factor

点击翻译按钮获取中文摘要

We found previously that human skin fibroblasts and various human leukemia cell lines produce and secrete hepatocyte growth factor (HGF). We also reported that protein-kinase-C-activating agents, protein-kinase-A-activating agents and some growth factors stimulate HGF production in those cells, while TGF-beta and dexamethasone inhibit HGF production. In this study, I searched other regulators of HGF production and found that interferon-gamma (IFN-gamma) markedly increased HGF production in KG-1 and RPMI-8226 leukemia cell lines. HGF gene expression was also up-regulated by IFN-gamma. IFN-gamma was as effective as or more effective than other HGF inducers. IFN-alpha and IFN-beta also stimulate HGF production in both cell lines, but they were less effctive than IFN-gamma in KG-1 cells. HGF production in human skin fibroblasts, however, was only slightly stimulated by IFN-gamma but not by IFN-alpha and IFN-beta. However, WN-gamma synergistically enhanced HGF production induced by 8-bromo- … More cAMP in the fibroblasts. Neither IFN-alpha nor IFN-beta had such an enhancing effect, but both these IENs inhibited the synergistic effect of IFN-gamma and 8-bromo-cAMP.IFN-gamma also synergistically augmented HGF production induced by other cAMP-increasing agents and interleukin-1beta in the fibroblasts. The synergy between HGF inducers and IFN-gamma is not common to all HGF inducers, because HGF production stimulated by EGF and protein-kinase-C-activating phorbol esters was significantly inhibited by IFN-gamma One pathway for IFN-y stimulation of gene expression operates through an enhancer element known as the IFN-gamma-activated sequence (GAS). One GAS site, which matches the GAS consensus sequence, is located in the 5-flanking region of the human HGF gene. It is likely that the GAS sequence participates in the stimulation of HGF gene expression in response to IFN-gamma. The finding that IFN-gamma markedly stimulated HGF production suggests the presence of a homeostatic control mechanism in liver regeneration and repair : hepatic injury. DNA synthesis inhibition or apoptosis caused by IFN-gamma is subsequently overcome by cytokine-induced HGF.We reported previously that HGF production by human embryonic lung fibroblats increases in the process of aging in culture, In this study we found that this is mainly due to autocrine stimulation by interleukin-1. Less