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Inhibitor of apoptosis (IAP) proteins limit RIP3 dependent IL-1 activation


Vince, J E; Wong, W Wei-Lynn; Gentle, I E; Lawlor, K E; Allam, R; O'Reilly, L; Mason, K; Gross, O; Ma, S; Guarda, G; Anderton, H; Castillo, R; Häcker, G; Silke, J; Tschopp, J (2012). Inhibitor of apoptosis (IAP) proteins limit RIP3 dependent IL-1 activation. Immunity, 36(2):215-227.

Abstract

Interleukin-1b (IL-1b) is a potent inflammatory cyto- kine that is usually cleaved and activated by inflam- masome-associated caspase-1. To determine whether IL-1b 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-1b that was mediated not only by the NLRP3-caspase-1 inflammasome, but also by cas- pase-8 in a caspase-1-independent manner. In the absence of IAPs, rapid and full generation of active IL-1b by the NLRP3-caspase-1 inflammasome, or by caspase-8, required the kinase RIP3 and reactive oxygen species production. These results demon- strate that activation of the cell death-inducing ripop- tosome platform and RIP3 can generate bioactive IL-1b and implicate them as additional targets for the treatment of pathological IL-1-driven inflamma- tory responses.

Abstract

Interleukin-1b (IL-1b) is a potent inflammatory cyto- kine that is usually cleaved and activated by inflam- masome-associated caspase-1. To determine whether IL-1b 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-1b that was mediated not only by the NLRP3-caspase-1 inflammasome, but also by cas- pase-8 in a caspase-1-independent manner. In the absence of IAPs, rapid and full generation of active IL-1b by the NLRP3-caspase-1 inflammasome, or by caspase-8, required the kinase RIP3 and reactive oxygen species production. These results demon- strate that activation of the cell death-inducing ripop- tosome platform and RIP3 can generate bioactive IL-1b and implicate them as additional targets for the treatment of pathological IL-1-driven inflamma- tory responses.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:17 Jan 2013 13:49
Last Modified:07 Dec 2017 18:08
Publisher:Cell Press
ISSN:1074-7613
Publisher DOI:https://doi.org/10.1016/j.immuni.2012.01.012

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