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

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cell Line
  • Cytochrome c Group / metabolism
  • Enzyme Activation / physiology
  • Hepatocytes / drug effects*
  • Hepatocytes / physiology*
  • JNK Mitogen-Activated Protein Kinases
  • Mitochondria / enzymology
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology*
  • Proto-Oncogene Proteins c-jun / physiology*
  • Rats
  • Time Factors
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Transcription Factor AP-1 / genetics
  • Transcription, Genetic / physiology
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Cytochrome c Group
  • NF-kappa B
  • Proto-Oncogene Proteins c-jun
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases