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 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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Apoptosis Regulatory Proteins
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Baculoviral IAP Repeat-Containing 3 Protein
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Carrier Proteins / agonists
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Carrier Proteins / metabolism
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Caspase 1 / metabolism
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Inflammasomes / immunology
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Inflammasomes / metabolism
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors
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Inhibitor of Apoptosis Proteins / deficiency
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism*
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Interleukin-1beta / metabolism*
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Knockout
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Mitochondrial Proteins / agonists
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Molecular Mimicry
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NLR Family, Pyrin Domain-Containing 3 Protein
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Reactive Oxygen Species / metabolism
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
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Ubiquitin-Protein Ligases
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X-Linked Inhibitor of Apoptosis Protein / deficiency
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X-Linked Inhibitor of Apoptosis Protein / genetics
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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Carrier Proteins
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Diablo protein, mouse
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Inflammasomes
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Inhibitor of Apoptosis Proteins
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Interleukin-1beta
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Mitochondrial Proteins
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Reactive Oxygen Species
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X-Linked Inhibitor of Apoptosis Protein
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Baculoviral IAP Repeat-Containing 3 Protein
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Birc2 protein, mouse
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Birc3 protein, mouse
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Ubiquitin-Protein Ligases
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk3 protein, mouse
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Caspase 1