Journal article
Inhibitor of Apoptosis Proteins Limit RIP3 Kinase-Dependent Interleukin-1 Activation
JE Vince, WWL Wong, I Gentle, KE Lawlor, R Allam, L O'Reilly, K Mason, O Gross, S Ma, G Guarda, H Anderton, R Castillo, G Häcker, J Silke, J Tschopp
Immunity | Published : 2012
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 b..
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Awarded by European Molecular Biology Organization
Funding Acknowledgements
Thanks to M. McKinlay and S.K. Chunduru for Smac mimetic compound (TetraLogic Pharmaceuticals) and D. Vaux, M. Leverkus, K. Schroder, and B. Croker for advice. We would also like to thank D. Huang (Walter and Eliza Hall Institute, Australia) for providing Bax and Bak knockout mice, V. Dixit (Genentech, USA) for Ripk3<SUP>-/-</SUP> mice, A. Strasser (Walter and Eliza Hall Institute, Australia) for Bid<SUP>-/-</SUP> mice, H. Korner (James Cook University, Australia) for Tnf<SUP>-/-</SUP> and Tnfrsfla<SUP>-/-</SUP> mice, B. Crocker (Waiter and Eliza Hall Institute, Australia) for the pEF IL-1-FLAG cDNA, and E. Latz (University of Massachusetts Medical School, USA) for the v-myc/v-raf immortalized macrophages. J.E.V. was supported by Human Frontiers and NHMRC C. J. Martin fellowships. G.H. is supported by a Deutsche Krebshilfe/Mildred Scheel-Stiftung grant and I.G. is supported by an EMBO Long Term Fellowship. J.S. is on the scientific advisory board at TetraLogic pharmaceuticals and is supported by NHMRC grants 541901, 541902, and 602516. L.O. is supported by NHMRC grant 1009145. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.