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 g...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2012-02, Vol.36 (2), p.215-227
Main Authors: Vince, James E., Wong, W. Wei-Lynn, Gentle, Ian, Lawlor, Kate E., Allam, Ramanjaneyulu, O'Reilly, Lorraine, Mason, Kylie, Gross, Olaf, Ma, Stephen, Guarda, Greta, Anderton, Holly, Castillo, Rosa, Häcker, Georg, Silke, John, Tschopp, Jürg
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Baculoviral IAP Repeat-Containing 3 Protein
Carrier Proteins - agonists
Carrier Proteins - metabolism
Caspase 1 - metabolism
Caspase-1
Caspase-8
Cell activation
DIABLO protein
IAP protein
Immune system
Inflammasomes - immunology
Inflammasomes - metabolism
Inflammation
Inhibitor of Apoptosis Proteins - antagonists & inhibitors
Inhibitor of Apoptosis Proteins - deficiency
Inhibitor of Apoptosis Proteins - genetics
Inhibitor of Apoptosis Proteins - metabolism
Interleukin 1
Interleukin-1beta - metabolism
Macrophages
Macrophages - cytology
Macrophages - drug effects
Macrophages - immunology
Macrophages - metabolism
Mammals
Membranes
Mice
Mice, Knockout
Mitochondrial Proteins - agonists
Molecular Mimicry
NLR Family, Pyrin Domain-Containing 3 Protein
Proteins
Reactive oxygen species
Reactive Oxygen Species - metabolism
Receptor-Interacting Protein Serine-Threonine Kinases - metabolism
Toll-like receptors
Ubiquitin-Protein Ligases
X-Linked Inhibitor of Apoptosis Protein - deficiency
X-Linked Inhibitor of Apoptosis Protein - genetics
X-Linked Inhibitor of Apoptosis Protein - metabolism
XIAP protein
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Summary: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. [Display omitted] ► 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
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2012.01.012