NF-κB inactivation converts a hepatocyte cell line TNF-α response from proliferation to apoptosis

Yang Xu, Shani Bialik, Brett E. Jones, Yuji Iimuro, Richard N. Kitsis, Anu Srinivasan, David A. Brenner, Mark J. Czaja

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134 Scopus citations

Abstract

Toxins convert the hepatocellular response to tumor necrosis factor-α (TNF-α) stimulation from proliferation to cell death, suggesting that hepatotoxins somehow sensitize hepatocytes to TNF-α toxicity. Because nuclear factor-κB (NF-κB) activation confers resistance to TNF-α cytotoxicity in nonhepatic cells, the possibility that toxin-induced sensitization to TNF-α killing results from inhibition of NF-κB-dependent gene expression was examined in the RALA rat hepatocyte cell line sensitized to TNF-α cytotoxicity by actinomycin D (ActD). ActD did not affect TNF-α- induced hepatocyte NF-κB activation but decreased NF-κB-dependent gene expression. Expression of an IκB superrepressor rendered RALA hepatocytes sensitive to TNF-α-induced apoptosis in the absence of ActD. Apoptosis was blocked by caspase inhibitors, and TNF-α treatment led to activation of caspase-2, caspase-3, and caspase-8 only when NF-κB activation was blocked. Although apoptosis was blocked by the NF-κB-dependent factor nitric oxide (NO), inhibition of endogenous NO production did not sensitize cells to TNF- α-induced cytotoxicity. Thus NF-κB activation is the critical intracellular signal that determines whether TNF-α stimulates hepatocyte proliferation or apoptosis. Although exogenous NO blocks RALA hepatocyte TNF-α cytotoxicity, endogenous production of NO is not the mechanism by which NF-κB activation inhibits this death pathway.

Original languageEnglish (US)
Pages (from-to)C1058-C1066
JournalAmerican Journal of Physiology - Cell Physiology
Volume275
Issue number4 44-4
StatePublished - Oct 1 1998

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Keywords

  • Caspases
  • Hydrogen peroxide
  • Inducible nitric oxide synthase
  • Liver
  • Nitric oxide

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

Xu, Y., Bialik, S., Jones, B. E., Iimuro, Y., Kitsis, R. N., Srinivasan, A., Brenner, D. A., & Czaja, M. J. (1998). NF-κB inactivation converts a hepatocyte cell line TNF-α response from proliferation to apoptosis. American Journal of Physiology - Cell Physiology, 275(4 44-4), C1058-C1066.