TNFR80-dependent enhancement of TNFR60-induced cell death is mediated by TNFR-associated factor 2 and is specific for TNFR60

J Immunol. 1998 Sep 15;161(6):3136-42.

Abstract

Costimulation of TNFR80 can strongly enhance TNFR60-induced cell death. In this study, we show that this enhancement is TNFR60 selective, as neither TNF-related apoptosis-inducing ligand/Apo2 ligand-, Apo1/Fas-, ceramide-, nor daunorubicin-mediated cell death was affected by costimulation of TNFR80. We further demonstrate that TNFR-associated factor 2 (TRAF2) is critically involved in both negative and positive regulation of TNF-induced cell death. Overexpression of TRAF2 and of a TRAF2 mutant, deficient in nuclear factor-kappaB activation, selectively desensitized and enhanced, respectively, TNFR60-induced cell death in HeLa cells. However, upon costimulation of TNFR80, which mediates activation of nuclear factor-kappaB and the c-Jun amino-terminal kinase via TRAF2, TNF-induced cell death is drastically enhanced in parental and TRAF2-transfected, but not in TRAF2 (87-501)-transfected cells. These data point to a critical role of TRAF2 in the apoptotic TNFR cross talk, whereby the TNFR80-dependent enhancement of TNFR60-induced cell death is due to TNFR80-mediated negative regulation of TRAF2 function(s). An interference with TRAF2 function was confirmed independently by analysis of c-Jun amino-terminal kinase activation via TNFR60 upon prestimulation of TNFR80. We propose that the apoptotic TNFR cross talk is based on TNFR80-mediated abrogation of antiapoptotic TRAF2-dependent signaling pathways initiated by TNFR60, but not Apo1/Fas or the apoptotic TNF-related apoptosis-inducing ligand receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / physiology*
  • Antigens, CD / chemistry
  • Antigens, CD / metabolism
  • Antigens, CD / physiology*
  • Apoptosis Regulatory Proteins
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology*
  • Cell Death / drug effects
  • Cell Death / immunology
  • Ceramides / pharmacology
  • Daunorubicin / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • HeLa Cells / drug effects
  • HeLa Cells / immunology*
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Ligands
  • Membrane Glycoproteins / physiology
  • Mitogen-Activated Protein Kinases*
  • Receptors, Tumor Necrosis Factor / chemistry
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor / physiology*
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • TNF Receptor-Associated Factor 2
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins*
  • Tumor Necrosis Factor-alpha / physiology
  • fas Receptor / physiology

Substances

  • Adjuvants, Immunologic
  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Ceramides
  • Ligands
  • Membrane Glycoproteins
  • PSMD2 protein, human
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • TNF Receptor-Associated Factor 2
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Daunorubicin