title: Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation.
abstract: Interleukin-1β (IL-1β) is a potent inflammatory cytokine that is usually cleaved and activated by inflammasome-associated caspase-1. To determine whether IL-1β activation is regulated by inhibitor of apoptosis (IAP) proteins, we treated macrophages with an IAP-antagonist "Smac mimetic" compound or genetically deleted the genes that encode the three IAP family members cIAP1, cIAP2, and XIAP. After Toll-like receptor priming, IAP inhibition triggered cleavage of IL-1β that was mediated not only by the NLRP3-caspase-1 inflammasome, but also by caspase-8 in a caspase-1-independent manner. In the absence of IAPs, rapid and full generation of active IL-1β by the NLRP3-caspase-1 inflammasome, or by caspase-8, required the kinase RIP3 and reactive oxygen species production. These results demonstrate that activation of the cell death-inducing ripoptosome platform and RIP3 can generate bioactive IL-1β and implicate them as additional targets for the treatment of pathological IL-1-driven inflammatory responses.
authors.affiliation: Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland. vince@wehi.edu.au
authors.forename: James E
authors.initials: JE
authors.lastname: Vince
authors.forename: W Wei-Lynn
authors.initials: WW
authors.lastname: Wong
authors.forename: Ian
authors.initials: I
authors.lastname: Gentle
authors.forename: Kate E
authors.initials: KE
authors.lastname: Lawlor
authors.forename: Ramanjaneyulu
authors.initials: R
authors.lastname: Allam
authors.forename: Lorraine
authors.initials: L
authors.lastname: O'Reilly
authors.forename: Kylie
authors.initials: K
authors.lastname: Mason
authors.forename: Olaf
authors.initials: O
authors.lastname: Gross
authors.forename: Stephen
authors.initials: S
authors.lastname: Ma
authors.forename: Greta
authors.initials: G
authors.lastname: Guarda
authors.forename: Holly
authors.initials: H
authors.lastname: Anderton
authors.forename: Rosa
authors.initials: R
authors.lastname: Castillo
authors.forename: Georg
authors.initials: G
authors.lastname: Häcker
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002352:Carrier Proteins / Q000819:agonists / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000819:agonists; D018716:Molecular Mimicry; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D058847:Inflammasomes; D051034:Inhibitor of Apoptosis Proteins; D053583:Interleukin-1beta; D024101:Mitochondrial Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D051636:X-Linked Inhibitor of Apoptosis Protein; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494834:Birc2 protein, mouse; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D020170:Caspase 1