Liu Hailing, Lo Chau R, Czaja Mark J
Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Hepatology. 2002 Apr;35(4):772-8. doi: 10.1053/jhep.2002.32534.
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-Jun NH(2)-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.
肝细胞对肿瘤坏死因子α（TNF）诱导的凋亡具有抗性，这依赖于转录因子核因子κB（NF-κB）的激活。为了确定NF-κB抵御TNF毒性的机制，在大鼠肝细胞系RALA255-10G中检测了NF-κB失活对促凋亡的c-Jun氨基末端激酶（JNK）信号通路的影响。腺病毒介导的NF-κB失活导致JNK的持续激活，并增加了对TNF处理的反应中激活蛋白-1（AP-1）的转录活性。通过细胞存活、凋亡和坏死细胞数量以及DNA亚二倍体的检测发现，抑制JNK底物和AP-1亚基c-Jun的功能可阻止因NF-κB失活和TNF导致的细胞死亡。抑制c-Jun功能可阻止线粒体细胞色素c的释放以及caspase-3和-7的激活。因此，NF-κB通过下调JNK和c-Jun/AP-1来阻断TNF死亡通路。总之，在没有NF-κB的情况下发生的持续JNK激活通过c-Jun依赖的线粒体死亡通路诱导启动凋亡。
