Control of ER stress by a chemical chaperone counteracts apoptotic signals in IFN-γ-treated murine hepatocytes
Control of ER stress by a chemical chaperone counteracts apoptotic signals in IFN-γ-treated murine hepatocytes
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DOI：
10.1007/s10495-009-0318-x
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发表时间：
2009-03-01
期刊：
影响因子：
7.2
通讯作者：
Watanabe, Yoshifumi
中科院分区：
文献类型：
--
作者：
Kanki, Keita;Kawamura, Takeshi;Watanabe, Yoshifumi
肝细胞凋亡在免疫性肝炎的发病机制中起着关键作用。然而，凋亡信号转导的详细机制仍不清楚。在这项研究中，我们研究了参与ER应力在IFN-γ诱导的肝细胞凋亡模型在体外，使用化学伴侣试剂，甘油。IFN-γ诱导的细胞凋亡事件（线粒体释放细胞色素c，半胱天冬酶-3和-9的酶促激活）被甘油显着抑制。甘油诱导的细胞毒性的部分抑制乳酸脱氢酶从胞质溶胶中释放，但没有抑制作用的诱导IRF-1基因表达和活性氧，所需的肝细胞凋亡的IFN-γ。caspase-4和-12基因表达的诱导，与ER应激呈正相关，甘油减弱。基因分析显示，ER应激相关基因C/EBP同源蛋白（CHOP/GADD 153）和TRB 3的诱导被甘油处理完全抑制。这些结果表明，ER应激在介导IFN-γ诱导的肝细胞凋亡中起着至关重要的作用，化学伴侣是ER应激的有效抑制剂。
Apoptosis of hepatocytes plays a key role in the pathogenesis of immune-mediated hepatitis. However, the detailed mechanisms of apoptotic signaling remain unclear. In this study, we investigated the involvement of ER stress in a model of IFN-gamma-induced apoptosis of hepatocytes in vitro, using a chemical chaperone reagent, glycerol. IFN-gamma-induced apoptotic events (mitochondrial release of cytochrome c, enzymatic activation of caspase-3 and -9) were markedly inhibited by glycerol. Glycerol induced partial inhibition of cytotoxicity indicated by lactate dehydrogenase release from the cytosol but had no inhibitory effect on the induction of IRF-1 gene expression and reactive oxygen species, required for hepatocyte apoptosis by IFN-gamma. Induction of caspase-4 and -12 gene expression, positively correlated with ER stress, was attenuated by glycerol. Gene analysis revealed that induction of ER stress-related genes, C/EBP homologue protein (CHOP/GADD153) and TRB3, was suppressed completely by glycerol treatment. These results suggest that ER stress plays a crucial role in mediating apoptosis of hepatocytes induced by IFN-gamma, and a chemical chaperone is an effective inhibitor of the ER stress.