NF-kappaB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun.
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.
Liu
Hailing
H
Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Lo
Chau R
CR
Czaja
Mark J
MJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D008928:Mitochondria / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D051381:Rats; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D003574:Cytochrome c Group; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases