Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production

Cell Death Differ. 2015 Aug;22(8):1313-27. doi: 10.1038/cdd.2014.222. Epub 2015 Jan 23.


TNF promotes a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing RIPK3. Because necrosis is generally more pro-inflammatory than apoptosis, it is widely presumed that TNF-induced necroptosis may be detrimental in vivo due to excessive inflammation. However, because TNF is intrinsically highly pro-inflammatory, due to its ability to trigger the production of multiple cytokines and chemokines, rapid cell death via necroptosis may blunt rather than enhance TNF-induced inflammation. Here we show that TNF-induced necroptosis potently suppressed the production of multiple TNF-induced pro-inflammatory factors due to RIPK3-dependent cell death. Similarly, necroptosis also suppressed LPS-induced pro-inflammatory cytokine production. Consistent with these observations, supernatants from TNF-stimulated cells were more pro-inflammatory than those from TNF-induced necroptotic cells in vivo. Thus necroptosis attenuates TNF- and LPS-driven inflammation, which may benefit intracellular pathogens that evoke this mode of cell death by suppressing host immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Apoptosis / physiology
  • Cell Line
  • Chemokines / metabolism*
  • Cytokines / metabolism*
  • Humans
  • Lipopolysaccharides / pharmacology*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Chemokines
  • Cytokines
  • Lipopolysaccharides
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • MLKL protein, human
  • Protein Kinases
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases