title: Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production.
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.
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin D2, Ireland.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kearney
authors.affiliation: 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.
authors.forename: S P
authors.initials: SP
authors.lastname: Cullen
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin D2, Ireland.
authors.forename: G A
authors.initials: GA
authors.lastname: Tynan
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin D2, Ireland.
authors.forename: C M
authors.initials: CM
authors.lastname: Henry
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin D2, Ireland.
authors.forename: D
authors.initials: D
authors.lastname: Clancy
authors.affiliation: 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.
authors.forename: E C
authors.initials: EC
authors.lastname: Lavelle
authors.affiliation: 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.
authors.forename: S J
authors.initials: SJ
authors.lastname: Martin
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C570693:MLKL protein, human; D011494:Protein Kinases; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases