NF-κB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun
NF-κB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun
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DOI：
10.1053/jhep.2002.32534
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发表时间：
2002-04-01
期刊：
影响因子：
13.5
通讯作者：
Czaja, MJ
中科院分区：
文献类型：
--
作者：
Liu, HL;Lo, CR;Czaja, MJ
肝细胞对肿瘤坏死因子α（TNF）诱导的细胞凋亡的抵抗依赖于转录因子核因子κ B（NF-κ B）的激活。为了确定NF-κ B保护免受TNF毒性的机制，在大鼠肝细胞系RALA 255 - 10 G中检查NF-κ B失活对促凋亡c-Ju NH 2-末端激酶（JNK）信号传导途径的影响。腺病毒介导的NF-kappaB失活导致JNK激活延长，并增加激活蛋白-1（AP-1）的转录活性，以响应TNF治疗。JNK底物和AP-1亚基c-Jun功能的抑制阻断了由NF-κ B失活和TNF引起的细胞死亡，如通过测量细胞存活、凋亡和坏死细胞的数量以及DNA亚倍体所确定的。抑制c-jun功能可阻断线粒体细胞色素c的释放和caspase-3和-7的激活。因此，NF-κ B通过下调JNK和c-Jun/AP-1阻断TNF死亡途径。总之，持续的JNK激活，发生在NF-κ B的情况下启动细胞凋亡通过c-Jun依赖性诱导线粒体死亡途径。
Hepatocyte resistance to tumor necrosis factor alpha(TNF)-induced apoptosis is dependent on activation of the transcription factor nuclear factor kappaB (NF-kappaB). To determine the mechanism by which NF-kappaB protects against TNF toxicity, the effect of NF-kappaB inactivation on the proapoptotic c-Ju NH2-terminal kinase (JNK) signaling pathway was examined in the rat hepatocyte cell line RALA255-10G. Adenovirus-mediated NF-kappaB inactivation led to a prolonged activation of JNK and increased activating protein-1 (AP-1) transcriptional activity in response to TNF treatment. Inhibition of the function of the JNK substrate and AP-1 subunit c-Jun blocked cell death from NF-kappaB inactivation and TNF as determined by measures of cell survival, numbers of apoptotic and necrotic cells, and DNA hypoploidy. Inhibition of c-jun function blocked mitochondrial cytochrome c release and activation of caspase-3 and -7. NF-kappaB therefore blocks the TNF death pathway through down-regulation of JNK and c-Jun/AP-1. In conclusion, sustained JNK activation that occurs in the absence of NF-kappaB initiates apoptosis through a c-Jun-dependent induction of the mitochondrial death pathway.