CpG DNA-mediated induction of acute liver injury in D-galactosamine-sensitized mice: the mitochondrial apoptotic pathway-dependent death of hepatocytes.
CpG DNA-mediated induction of acute liver injury in D-galactosamine-sensitized mice: the mitochondrial apoptotic pathway-dependent death of hepatocytes.
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CpG DNA 介导的 D-半乳糖胺致敏小鼠急性肝损伤诱导：肝细胞线粒体凋亡途径依赖性死亡。
DOI：
10.1074/jbc.m601337200
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Martinez-Hernandez,Antonio
中科院分区：
文献类型：
--
作者：
Yi,Ae-Kyung;Yoon,Hyunsook;Park,Jeoung-Eun;Kim,Beom-Sue;Kim,HaeJong;Martinez-Hernandez,Antonio
存在于细菌DNA（CpG DNA）中的未甲基化CpG基序诱导先天性炎症反应，包括快速诱导促炎细胞因子。尽管由CpG DNA和其他病原体相关分子模式诱导的先天性炎症反应对于根除感染性微生物是必不可少的，但先天免疫的过度激活对宿主是有害的。在这项研究中，我们证明，CpG DNA，而不是控制非CpG DNA，诱导暴发性肝衰竭，随后休克介导的死亡，促进肝细胞的大量凋亡ind-galactosamine（d-GalN）致敏小鼠。抑制线粒体膜通透性转换孔开放或caspase 9活性可保护d-GalN致敏小鼠免受CpG DNA介导的肝损伤和死亡。CpG DNA通过TLR 9/MyD 88依赖性途径增强ind-GalN致敏小鼠促炎细胞因子的产生此外，CpG DNA未能诱导大量肝细胞凋亡和随后的暴发性肝功能衰竭和死亡ind-GalN致敏小鼠，这些小鼠缺乏TLR 9、MyD 88、肿瘤坏死因子（TNF）-α或TNF受体I，但不缺乏白细胞介素-6或-12p40。综上所述，我们的结果提供了直接证据，即CpG DNA通过TLR 9/MyD 88信号通路增强TNF-α的产生引起肝细胞的线粒体凋亡通路依赖性死亡诱导严重的急性肝损伤和休克介导的死亡。
Unmethylated CpG motifs present in bacterial DNA (CpG DNA) induce innate inflammatory responses, including rapid induction of proinflammatory cytokines. Although innate inflammatory responses induced by CpG DNA and other pathogen-associated molecular patterns are essential for the eradication of infectious microorganisms, excessive activation of innate immunity is detrimental to the host. In this study, we demonstrate that CpG DNA, but not control non-CpG DNA, induces a fulminant liver failure with subsequent shock-mediated death by promoting massive apoptotic death of hepatocytes ind-galactosamine (d-GalN)-sensitized mice. Inhibition of mitochondrial membrane permeability transition pore opening or caspase 9 activityin vivoprotectsd-GalN-sensitized mice from the CpG DNA-mediated liver injury and death. CpG DNA enhanced production of proinflammatory cytokines ind-GalN-sensitized mice via a TLR9/MyD88-dependent pathway. In addition, CpG DNA failed to induce massive hepatocyte apoptosis and subsequent fulminant liver failure and death ind-GalN-sensitized mice that lack TLR9, MyD88, tumor necrosis factor (TNF)-α, or TNF receptor I but not interleukin-6 or -12p40. Taken together, our results provide direct evidence that CpG DNA induces a severe acute liver injury and shock-mediated death through the mitochondrial apoptotic pathway-dependent death of hepatocytes caused by an enhanced production of TNF-α through a TLR9/MyD88 signaling pathway ind-GalN-sensitized mice.