Inhibitor of Apoptosis Proteins Limit RIP3 Kinase-Dependent Interleukin-1 Activation
- Author(s)
- Vince, JE; Wong, WWL; Gentle, I; Lawlor, KE; Allam, R; O'Reilly, L; Mason, K; Gross, O; Ma, S; Guarda, G; Anderton, H; Castillo, R; Hacker, G; Silke, J; Tschopp, J;
- Details
- Publication Year 2012-02-24,Volume 36,Issue #2,Page 215-227
- Journal Title
- IMMUNITY
- Publication Type
- Journal Article
- Abstract
- Interleukin-1 beta (IL-1 beta) is a potent inflammatory cytokine that is usually cleaved and activated by inflammasome-associated caspase-1. To determine whether IL-1 beta 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-1 beta 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-1 beta 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-1 beta and implicate them as additional targets for the treatment of pathological IL-1-driven inflammatory responses.
- Publisher
- CELL PRESS
- Keywords
- NF-KAPPA-B; STERILE INFLAMMATORY RESPONSE; NLRP3 INFLAMMASOME; TNF-ALPHA; PROGRAMMED NECROSIS; NALP3 INFLAMMASOME; CELL-DEATH; CASPASE-8; CIAP1; IL-1-BETA
- Research Division(s)
- Molecular Genetics Of Cancer; Cell Signalling And Cell Death
- Publisher's Version
- https://doi.org/10.1016/j.immuni.2012.01.012
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Creation Date: 2012-02-24 12:00:00