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Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation.
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.
Animals, Apoptosis, Carrier Proteins/agonists, Carrier Proteins/metabolism, Caspase 1/metabolism, Inflammasomes/immunology, Inflammasomes/metabolism, Inhibitor of Apoptosis Proteins/antagonists & inhibitors, Inhibitor of Apoptosis Proteins/deficiency, Interleukin-1beta/metabolism, Macrophages/cytology, Macrophages/drug effects, Mice, Mice, Knockout, Mitochondrial Proteins/agonists, Molecular Mimicry, Reactive Oxygen Species/metabolism, Receptor-Interacting Protein Serine-Threonine Kinases/metabolism, X-Linked Inhibitor of Apoptosis Protein/deficiency, X-Linked Inhibitor of Apoptosis Protein/genetics
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