Fatal hepatitis mediated by tumor necrosis factor TNFalpha requires caspase-8 and involves the BH3-only proteins Bid and Bim.
Fatal hepatitis mediated by tumor necrosis factor TNFalpha requires caspase-8 and involves the BH3-only proteins Bid and Bim.
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DOI：
10.1016/j.immuni.2008.10.017
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发表时间：
2009-01-16
期刊：
影响因子：
32.4
通讯作者：
Strasser, Andreas
中科院分区：
文献类型：
--
作者：
Kaufmann, Thomas;Jost, Philipp J.;Pellegrini, Marc;Puthalakath, Hamsa;Gugasyan, Raffi;Gerondakis, Steve;Cretney, Erika;Smyth, Mark J.;Silke, John;Hakem, Razq;Bouillet, Philippe;Mak, Tak W.;Dixit, Vishva M.;Strasser, Andreas
肝细胞凋亡是许多慢性和急性肝病的特征和促成因素，可能是免疫系统过度激活的结果。注射脂多糖（LPS）和转录抑制剂D（+）-半乳糖胺（GalN）或促有丝分裂T细胞活化可导致小鼠致命的肝细胞凋亡。在这两种情况下，肝细胞杀伤均由TNFα/TNF-R信号转导介导，但效应机制仍不清楚。我们对基因靶向小鼠的分析表明，在这两种情况下，caspase-8对肝细胞杀伤至关重要。Bid的损失，促凋亡的BH 3-唯一的蛋白激活的半胱天冬酶-8，和Fas配体诱导的肝细胞杀伤所必需的，导致肝损伤的轻微减少。然而，Bid和另一种由JNK激活的仅BH 3蛋白Bim的组合损失保护小鼠免受LPS+ GalN诱导的肝炎。这些观察结果将胱天蛋白酶-8和BH 3-only蛋白Bid和Bim鉴定为用于治疗炎性肝病的潜在治疗靶点。
Apoptotic death of hepatocytes, a feature and contributing factor of many chronic and acute liver diseases, can be a consequence of over-activation of the immune system. Injection with lipopolysaccharide (LPS) plus the transcriptional inhibitor D(+)-galactosamine (GalN) or mitogenic T cell activation cause fatal hepatocyte apoptosis in mice. In both settings hepatocyte killing is mediated by TNFα/TNF-R signaling but the effector mechanisms remain unclear. Our analysis of gene-targeted mice showed that caspase-8 is essential for hepatocyte killing in both settings. Loss of Bid, the pro-apoptotic BH3-only protein activated by caspase-8, and essential for Fas ligand-induced hepatocyte killing, resulted only in a minor reduction of liver damage. However, combined loss of Bid and another BH3-only protein, Bim, activated by JNK, protected mice from LPS+GalN-induced hepatitis. These observations identify caspase-8 and the BH3-only proteins Bid and Bim as potential therapeutic targets for treatment of inflammatory liver diseases.
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影响因子：
5.4
作者：
Kusters, S;Tiegs, G;Grell, M
通讯作者：
Grell, M
影响因子：
16.2
作者：
Putcha, GV;Le, SY;Johnson, EM
通讯作者：
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影响因子：
6
作者：
O'Reilly, LA;Cullen, L;Strasser, A
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影响因子：
64.8
作者：
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通讯作者：
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DOI：
10.1073/pnas.0438011100
发表时间：
2003-03-04
影响因子：
11.1
作者：
Lei, K;Davis, RJ
通讯作者：
Davis, RJ