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

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

Author information

1
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin D2, Ireland.
2
1] Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin D2, Ireland [2] Immunology Research Centre, Trinity College, Dublin D2, Ireland.
3
Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin D2, Ireland.
4
1] Immunology Research Centre, Trinity College, Dublin D2, Ireland [2] Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin D2, Ireland.

Abstract

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.

PMID:
25613374
PMCID:
PMC4495357
DOI:
10.1038/cdd.2014.222
[Indexed for MEDLINE]
Free PMC Article

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