Inhibitor of Apoptosis Proteins Limit RIP3 Kinase-Dependent Interleukin-1 Activation
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
WEHI Research Division(s)
Molecular Genetics Of Cancer; Cell Signalling And Cell Death
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Creation Date: 2012-02-24 12:00:00
Last Modified: 0001-01-01 12:00:00
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