The absence of NF-kappaB-mediated inhibition of c-Jun N-terminal kinase activation contributes to tumor necrosis factor alpha-induced apoptosis

Mol Cell Biol. 2002 Dec;22(24):8571-9. doi: 10.1128/mcb.22.24.8571-8579.2002.

Abstract

The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) regulates immune responses, inflammation, and programmed cell death (apoptosis). TNF-alpha exerts its biological activities by activating multiple signaling pathways, including IkappaB kinase (IKK), c-Jun N-terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the transcription factor NF-kappaB, whose target genes include those that encode inhibitors of both caspases and JNK. Despite activation of the antiapoptotic IKK/NF-kappaB pathway, TNF-alpha is able to induce apoptosis in cells sensitive to it, such as human breast carcinoma MCF-7 and mouse fibroblast LM cells. The molecular mechanism underlying TNF-alpha-induced apoptosis is incompletely understood. Here we report that in TNF-alpha-sensitive cells activation of the IKK/NF-kappaB pathway fails to block TNF-alpha-induced apoptosis, although its inactivation still promotes TNF-alpha-induced apoptosis. Interestingly, TNF-alpha-induced apoptosis is suppressed by inhibition of the JNK pathway but promoted by its activation. Furthermore, activation of JNK by TNF-alpha was transient in TNF-alpha-insensitive cells but prolonged in sensitive cells. Conversion of JNK activation from prolonged to transient suppressed TNF-alpha-induced apoptosis. Thus, absence of NF-kappaB-mediated inhibition of JNK activation contributes to TNF-alpha-induced apoptosis.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cell Line
  • Enzyme Activation
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Interleukin-1 / metabolism
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Tetradecanoylphorbol Acetate / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • I-kappa B Proteins
  • Interleukin-1
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate