Nuclear factor kB-independent cytoprotective pathways originating at tumor necrosis factor receptor-associated factor

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G Natoli1, A Costanzo, F Guido

  • 1Fondazione Andrea Cesalpino, Policlinico Umberto I, University of Rome La Sapienza, Viale del Policlinico 155, 00161 Rome, Italy.

The Journal of Biological Chemistry
|November 13, 1998
PubMed

Insights

Tumor necrosis factor (TNF) resistance in cells requires TNF receptor-associated factor 2 (TRAF2). NFkB-independent pathways are not the main mechanism for TNF cytoprotection.

Area of Science:

  • Cellular biology
  • Immunology
  • Molecular signaling

Background:

  • Most cells resist tumor necrosis factor (TNF) cytotoxicity without protein/RNA synthesis inhibitors.
  • Cellular resistance to TNF involves TNF receptor-associated factor 2 (TRAF2), linked to nuclear factor kB (NFkB) and activator protein 1 (AP1) activation.
  • NFkB was hypothesized to induce anti-apoptotic genes, but NFkB-independent pathways' roles are unclear.

Purpose of the Study:

  • To investigate NFkB-independent cytoprotective pathways against TNF cytotoxicity.
  • To compare the effects of NFkB pathway inhibitors versus TRAF2 signaling inhibitors on TNF cytotoxicity.
  • To elucidate the precise role of TRAF2 and other TNF receptor 1 complex components in cellular protection.

Main Methods:

  • Systematic comparison of selective trans-dominant NFkB pathway inhibitors with TRAF2 signaling inhibitors.
  • Assessment of TNF cytotoxicity in cells treated with various signaling pathway modulators.
  • Analysis of TRAF2 function using signaling-deficient oligomerization partners and molecules affecting TRAF2 recruitment.
  • Overexpression of TRAF2 in transfected cells to evaluate its sufficiency for cytoprotection.

Main Results:

  • Complete abrogation of TNF cytoprotection upon blockade of TRAF2 function or its recruitment to the TNF receptor 1 complex.
  • Selective NFkB blockade sensitized only a fraction of TNF-treated cells, suggesting a stochastic effect.
  • No cytoprotective role was found for c-Jun amino-terminal kinases/stress-activated protein kinases (JNKs/SAPKs).
  • Overexpressed TRAF2 alone was insufficient for cytoprotection, highlighting the necessity of other TNF receptor 1 complex components.

Conclusions:

  • TNF-induced cytoprotection is a complex process, not solely reliant on NFkB activation.
  • TRAF2 is essential but not sufficient for TNF cytoprotection, indicating the involvement of multiple signaling pathways.
  • The integration of multiple signal transduction pathways is critical for TNF-induced cytoprotection.

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