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

SummaryInterleukin-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.

Graphical AbstractFigure optionsDownload high-quality image (137 K)Download as PowerPoint slideHighlights
► IAP inhibition induces NLRP3 inflammasome-dependent and -independent IL-1 activation
► Genetic deletion of the three IAPs (cIAP1, cIAP2, XIAP) activates IL-1
► Inflammasome-independent IL-1 maturation is mediated by caspase-8 cleavage
► RIP3 signaling, and not cell death, activates IL-1