CpG DNA-mediated Induction of Acute Liver Injury in d-Galactosamine-sensitized Mice
CpG DNA-mediated Induction of Acute Liver Injury in d-Galactosamine-sensitized Mice
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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
DOI：
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发表时间：
2006
影响因子：
4.8
通讯作者：
A. Martinez‐Hernandez
中科院分区：
文献类型：
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作者：
A. Yi;Hyunsook Yoon;Jeoung;B. Kim;Hae Jong Kim;A. Martinez‐Hernandez
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，诱导暴发性肝功能衰竭，随后休克介导的死亡，促进大规模的肝细胞凋亡死亡的d-半乳糖胺（d-GalN）致敏小鼠。抑制线粒体膜通透性转换孔开放或caspase 9活性在体内保护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d-GalN致敏小鼠促炎细胞因子的产生此外，在缺乏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-12 p40的d-GalN致敏小鼠中，CpG DNA未能诱导大量肝细胞凋亡以及随后的爆发性肝衰竭和死亡。综上所述，我们的结果提供了直接证据，即CpG DNA通过d-GalN致敏小鼠中TLR 9/MyD 88信号通路引起的TNF-α产生增强引起的肝细胞线粒体凋亡通路依赖性死亡诱导严重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 in d-galactosamine (d-GalN)-sensitized mice. Inhibition of mitochondrial membrane permeability transition pore opening or caspase 9 activity in vivo protects d-GalN-sensitized mice from the CpG DNA-mediated liver injury and death. CpG DNA enhanced production of proinflammatory cytokines in d-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 in d-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 in d-GalN-sensitized mice.
IFN-γ 响应细菌 DNA 和寡脱氧核苷酸中的 CpG 基序，促进 IL-6 和 IgM 分泌。
DOI：
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发表时间：
1996
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
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作者：
Yi,AK;Chace,JH;Cowdery,JS;Krieg,AM
通讯作者：
Krieg,AM
通过免疫刺激 CpG DNA 快速诱导丝裂原激活蛋白激酶。
DOI：
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发表时间：
1998
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Yi,AK;Krieg,AM
通讯作者：
Krieg,AM