Tumor necrosis factor alpha mediates the lethal hepatotoxic effects of poly(I:C) in D-galactosamine-sensitized mice
Tumor necrosis factor alpha mediates the lethal hepatotoxic effects of poly(I:C) in D-galactosamine-sensitized mice
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DOI：
10.1016/j.cyto.2008.01.014
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发表时间：
2008-04-01
期刊：
影响因子：
3.8
通讯作者：
Libert, Claude
中科院分区：
文献类型：
--
作者：
Dejager, Lien;Libert, Claude
微生物病原体的保守分子模式，如脂多糖（LPS）和胞嘧啶 - 磷酸 - 鸟嘌呤（CpG）DNA基序，是先天免疫细胞受体介导激活的重要信号。已经表明，肝脏特异性转录阻断剂D - 半乳糖胺（D - GalN）会使机体对LPS和CpG DNA的致死效应高度敏感。在GalN处理的小鼠中，LPS或CpG DNA的致死性完全是由于肿瘤坏死因子 - α（TNF - α），它会导致肝细胞凋亡和急性肝衰竭。我们报道，多聚肌苷酸 - 多聚胞苷酸[poly(I:C)]，一种Toll样受体3（TLR - 3）激动剂，也会在小鼠体内诱导全身性TNF。在D - GalN致敏小鼠中，LPS、CpG DNA和poly(I:C)所诱导的肝酶升高以及死亡诱导作用，被中和性抗TNF - α抗体完全阻断，并且在TNF受体p55基因敲除小鼠中不存在。我们的研究结果提供了直接证据，表明poly(I:C)在D - GalN致敏小鼠中诱导TNF - α，从而导致严重、急性且依赖TNF的致死性肝炎。（c）2008爱思唯尔有限公司。保留所有权利。
Conserved molecular patterns of microbial pathogens, such as lipopolysaccharide (LPS) and cytosine-phosphate-guanine (CpG) DNA motifs are important signals for receptor-mediated activation of innate immune cells. It has been shown that the liver-specific transcription-blocking D-galactosamine (D-GalN) severely sensitizes to the lethal effects of LPS and CpG DNA. Lethality of LPS or CpC DNA in GalN-treated mice is entirely due to TNF-alpha, which leads to liver cell apoptosis and acute liver failure. We report that also polyinosinic-polycytidylic acid [poly(I:C)], a TLR-3 agonist, induces systemic TNF in mice. The increases of hepatic enzymes and induction of death induced by LPS, CpG DNA, and poly(I:C) in D-GalN sensitized mice are completely blocked by neutralizing anti-TNF-alpha antibodies and absent in TNF receptor p55-knockout mice. Our results provide direct evidence that poly(I:C) induces TNF-alpha in D-GalN sensitized mice, which leads to severe, acute, and TNF-dependent lethal hepatitis. (c) 2008 Elsevier Ltd. All rights reserved.