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

我们先前发现人皮肤成纤维细胞和各种人白血病细胞系产生和分泌肝细胞生长因子(HGF)。我们还报道了蛋白激酶C激动剂、蛋白激酶A激活剂和一些生长因子刺激这些细胞产生HGF，而转化生长因子-β和地塞米松则抑制HGF的产生。在这项研究中，我搜索了其他HGF产生的调节因素，发现干扰素-γ(IFN-Gamma)显著增加了KG-1和RPMI-8226白血病细胞系的HGF产生。干扰素-γ还可上调HGF基因的表达。干扰素-γ的作用与其他HGF诱导剂相同或更有效。干扰素-α和干扰素-β也能刺激两种细胞产生肝细胞生长因子，但对KG-1细胞的作用不如干扰素-γ。然而，人皮肤成纤维细胞中HGF的产生仅被干扰素-γ轻微刺激，而不是干扰素-α和干扰素-β。WN-γ协同增强8-溴-…诱导的肝细胞生长因子的产生成纤维细胞中有更多的cAMP。干扰素-α和干扰素-β均无此促进作用，但均抑制了干扰素-γ和8-溴环腺苷的协同作用。干扰素-γ还协同增强其他cAMP增强剂和白介素1-β诱导的成纤维细胞HGF的产生。HGF诱导剂和干扰素-γ之间的协同作用并不是所有的HGF诱导剂都通用的，因为由EGF和蛋白激酶C激活的佛波酯刺激的HGF的产生被干扰素-γ显著抑制。干扰素-γ刺激基因表达的一个途径是通过被称为干扰素-伽马激活序列(GAS)的增强子元件来操作的。一个与GAS共识序列匹配的GAS位点位于人类HGF基因的5-侧翼区。GAS序列可能参与了干扰素-γ刺激HGF基因表达的过程。这一发现显著刺激了HGF的产生，提示在肝脏再生和修复中存在一种动态平衡控制机制：肝脏损伤。干扰素-γ引起的DNA合成抑制或细胞凋亡随后被细胞因子诱导的HGF克服。我们先前报道，人胚胎肺成纤维细胞在培养的衰老过程中HGF的产生增加，在本研究中我们发现这主要是由于IL-1刺激的自分泌。较少

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