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

肝细胞生长因子诱导剂促进肝再生及肝损伤恢复的研究

• 批准号: 09672232
• 负责人: GOHDA Eiichi
• 金额: $ 2.37万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672232/
• 关键词: factor (HGF); Interferon-gamma; Interferon-alpha; Interferon-beta; Cyclic AMP; Human leukemia cells; Human skin fibroblasts; Liver regeneration; サイクリックAMP

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

我们以前发现，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激活剂、蛋白激酶A激活剂和一些生长因子刺激这些细胞中的HGF产生，而TGF-β和地塞米松抑制HGF产生。在这项研究中，我搜索了其他的HGF生产调节剂，发现干扰素-γ（IFN-γ）显着增加KG-1和RPMI-8226白血病细胞系的HGF生产。HGF基因表达也被IFN-γ上调。IFN-γ与其他HGF诱导剂一样有效或更有效。IFN-α和IFN-β也刺激两种细胞系中的HGF产生，但它们在KG-1细胞中的效果不如IFN-γ。然而，人皮肤成纤维细胞中的HGF产生仅被IFN-γ轻微刺激，而不被IFN-α和IFN-β刺激。然而，WN-γ协同增强由8-溴-1H-吡唑诱导的HGF产生。 ...更多信息 成纤维细胞中的cAMP。IFN-α和IFN-β都没有这种促进作用，但这两种IENs都抑制IFN-γ和8-溴-cAMP的协同作用，IFN-γ也协同促进成纤维细胞中由其他cAMP增加剂和白细胞介素-1 β诱导的HGF产生。HGF诱导剂和IFN-γ之间的协同作用并不常见于所有HGF诱导剂，因为EGF和蛋白激酶C激活佛波醇酯刺激的HGF产生被IFN-γ显著抑制。IFN-γ刺激基因表达的一条途径通过称为IFN-γ激活序列（GAS）的增强子元件起作用。与GAS共有序列匹配的一个GAS位点位于人HGF基因的5-侧翼区。很可能GAS序列参与了响应IFN-γ的HGF基因表达的刺激。IFN-γ显著刺激HGF产生的发现表明在肝再生和修复中存在稳态控制机制：肝损伤。IFN-γ引起的DNA合成抑制或细胞凋亡随后被苦参碱诱导的HGF所克服。我们以前报道过在培养的人胚肺成纤维细胞衰老过程中HGF的产生增加，在本研究中我们发现这主要是由于白细胞介素-1的自分泌刺激。少