Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway
Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway
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DOI：
10.1074/jbc.m512953200
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发表时间：
2006-06-02
影响因子：
4.8
通讯作者：
Czaja, Mark J.
中科院分区：
文献类型：
--
作者：
Wang, Yongjun;Singh, Rajat;Czaja, Mark J.
肝细胞的体外研究表明，c-Jun N-末端激酶（JNK）信号转导的过度激活是肿瘤坏死因子-α（TNF）诱导细胞凋亡的一种机制。然而，JNK激活的功能意义和特定JNK亚型在体内TNF诱导的肝细胞凋亡中的作用仍不清楚。因此，JNK 1和JNK 2的功能，在TNF-依赖性，半乳糖胺/脂多糖（GalN/LPS）模型的肝损伤进行了研究。毒素GalN将LPS诱导的JNK信号传导从短暂激活转变为长期激活。GalN/LPS引起的肝损伤和死亡率在野生型和jnk 1（-/-）小鼠中相当，但在jnk 2（-/-）小鼠中显著降低。这种作用不是继发于TNF受体1表达或TNF产生的下调。在不存在jnk 2的情况下，半胱天冬酶依赖性TNF死亡途径被阻断，如半胱天冬酶-3和-7和聚（ADP-核糖）聚合酶裂解发生的失败所反映的。JNK 2是激活线粒体死亡途径的关键，因为在JNK 2（-/-）小鼠中，Bid切割和线粒体易位以及细胞色素c释放显著减少。这种效应是次要的，因为jnk 2（-/-）小鼠未能激活caspase-8。在GalN/TNF处理后，jnk 2基因敲除小鼠的肝损伤和半胱天冬酶活化类似地降低。尽管jnk 1（-/-）小鼠的活性被完全阻断，但jnk 2的消融并没有抑制GalN/LPS诱导的c-Jun激酶活性。因此，毒性肝损伤与JNK过度活化相关，并通过JNK 2促进胱天蛋白酶-8活化和TNF线粒体死亡途径介导，其机制独立于c-Jun激酶活性。
In vitro studies of hepatocytes have implicated over-activation of c-Jun N-terminal kinase (JNK) signaling as a mechanism of tumor necrosis factor-alpha (TNF)-induced apoptosis. However, the functional significance of JNK activation and the role of specific JNK isoforms in TNF-induced hepatic apoptosis in vivo remain unclear. JNK1 and JNK2 function was, therefore, investigated in the TNF-dependent, galactosamine/lipopolysaccharide (GalN/LPS) model of liver injury. The toxin GalN converted LPS-induced JNK signaling from a transient to prolonged activation. Liver injury and mortality from GalN/LPS was equivalent in wild-type and jnk1(-/-) mice but markedly decreased in jnk2(-/-) mice. This effect was not secondary to down-regulation of TNF receptor 1 expression or TNF production. In the absence of jnk2, the caspase-dependent, TNF death pathway was blocked, as reflected by the failure of caspase-3 and -7 and poly(ADP-ribose) polymerase cleavage to occur. JNK2 was critical for activation of the mitochondrial death pathway, as in jnk2(-/-) mice Bid cleavage and mitochondrial translocation and cytochrome c release were markedly decreased. This effect was secondary to the failure of jnk2(-/-) mice to activate caspase-8. Liver injury and caspase activation were similarly decreased in jnk2 null mice after GalN/TNF treatment. Ablation of jnk2 did not inhibit GalN/LPS-induced c-Jun kinase activity, although activity was completely blocked in jnk1(-/-) mice. Toxic liver injury is, therefore, associated with JNK over-activation and mediated by JNK2 promotion of caspase-8 activation and the TNF mitochondrial death pathway through a mechanism independent of c-Jun kinase activity.