NF-κB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun

Hailing Liu, Chau R. Lo, Mark J. Czaja

Research output: Contribution to journalArticle

168 Scopus citations


Hepatocyte resistance to tumor necrosis factor α (TNF)-induced apoptosis is dependent on activation of the transcription factor nuclear factor κB (NF-κB). To determine the mechanism by which NF-κB protects against TNF toxicity, the effect of NF-κB inactivation on the proapoptotic c-Jun NH2-terminal kinase (JNK) signaling pathway was examined in the rat hepatocyte cell line RALA255-10G. Adenovirus-mediated NF-κB 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-κB 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-κB 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-κB initiates apoptosis through a c-Jun-dependent induction of the mitochondrial death pathway.

Original languageEnglish (US)
Pages (from-to)772-778
Number of pages7
Issue number4
StatePublished - Jan 1 2002


ASJC Scopus subject areas

  • Hepatology

Cite this