Inhibitor of Apoptosis Proteins Limit RIP3 Kinase-Dependent Interleukin-1 Activation

James E. Vince, W. Wei Lynn Wong, Ian Gentle, Kate E. Lawlor, Ramanjaneyulu Allam, Lorraine O'Reilly, Kylie Mason, Olaf Gross, Stephen Ma, Greta Guarda, Holly Anderton, Rosa Castillo, Georg Häcker, John Silke, Jürg Tschopp

Research output: Contribution to journalArticleResearchpeer-review

332 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)215-227
Number of pages13
JournalImmunity
Volume36
Issue number2
DOIs
Publication statusPublished - 24 Feb 2012
Externally publishedYes

Cite this