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

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Abstract

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
JournalHepatology
Volume35
Issue number4
DOIs
StatePublished - 2002

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JNK Mitogen-Activated Protein Kinases
Hepatocytes
Tumor Necrosis Factor-alpha
Apoptosis
Proto-Oncogene Proteins c-jun
Caspase 7
Protein Subunits
Cytochromes c
Adenoviridae
Caspase 3
Cell Survival
Cell Death
Transcription Factors
Down-Regulation
Cell Count
Cell Line
DNA
Proteins

ASJC Scopus subject areas

  • Hepatology

Cite this

NF-κB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun. / Liu, Hailing; Lo, Chau R.; Czaja, Mark J.

In: Hepatology, Vol. 35, No. 4, 2002, p. 772-778.

Research output: Contribution to journalArticle

Liu, Hailing ; Lo, Chau R. ; Czaja, Mark J. / NF-κB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun. In: Hepatology. 2002 ; Vol. 35, No. 4. pp. 772-778.
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N2 - 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.

AB - 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.

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