More to Life than NF-κB in TNFR1 Signaling

Trends Immunol. 2016 Aug;37(8):535-545. doi: 10.1016/ Epub 2016 Jul 13.


TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders has long been attributed to induction of proinflammatory mediators. TNF also activates cell survival and death pathways, and recent studies demonstrated that TNF also causes inflammation by inducing cell death. The default response of most cells to TNF is survival and NF-κB-mediated upregulation of prosurvival molecules is a well-documented protective mechanism downstream of TNFR1. Recent studies revealed the existence of an NF-κB-independent cell death checkpoint that restricts cell demise by inactivating RIPK1. Disruption of this checkpoint leads to RIPK1 kinase-dependent death and causes inflammation in vivo. These revelations bring complexity to the control of TNF-induced cell death, and suggest clinical benefit of RIPK1 inhibitors in TNF-driven human inflammatory disorders.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Cell Death
  • Cytokines / metabolism
  • Gene Expression Regulation
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation Mediators / metabolism
  • NF-kappa B / metabolism*
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Protein Binding
  • Protein Processing, Post-Translational
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Signal Transduction*


  • Biomarkers
  • Cytokines
  • Inflammation Mediators
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor, Type I