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

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

Research output: Contribution to journalArticle

133 Citations (Scopus)

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)
JournalAmerican Journal of Physiology
Volume275
Issue number4 PART 1
StatePublished - 1998

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Hepatocytes
Tumor Necrosis Factor-alpha
Apoptosis
Cell Line
Nitric Oxide
Dactinomycin
Hepatocyte Nuclear Factors
Caspase 2
Gene Expression
Caspase Inhibitors
Caspase 8
Caspase 3
Cell Death

Keywords

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

ASJC Scopus subject areas

  • Physiology (medical)

Cite this

Yang, X. U., Bialik, S., Jones, B. E., Iimuro, Y., Kitsis, R. N., Srinivasan, A., ... Czaja, M. J. (1998). NF-κB inactivation converts a hepatocyte cell line TNF-α response from proliferation to apoptosis. American Journal of Physiology, 275(4 PART 1).

NF-κB inactivation converts a hepatocyte cell line TNF-α response from proliferation to apoptosis. / Yang, X. U.; Bialik, Shani; Jones, Brett E.; Iimuro, Yuji; Kitsis, Richard N.; Srinivasan, Anu; Brenner, David A.; Czaja, Mark J.

In: American Journal of Physiology, Vol. 275, No. 4 PART 1, 1998.

Research output: Contribution to journalArticle

Yang, XU, Bialik, S, Jones, BE, Iimuro, Y, Kitsis, RN, Srinivasan, A, Brenner, DA & Czaja, MJ 1998, 'NF-κB inactivation converts a hepatocyte cell line TNF-α response from proliferation to apoptosis', American Journal of Physiology, vol. 275, no. 4 PART 1.
Yang, X. U. ; Bialik, Shani ; Jones, Brett E. ; Iimuro, Yuji ; Kitsis, Richard N. ; Srinivasan, Anu ; Brenner, David A. ; Czaja, Mark J. / NF-κB inactivation converts a hepatocyte cell line TNF-α response from proliferation to apoptosis. In: American Journal of Physiology. 1998 ; Vol. 275, No. 4 PART 1.
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