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Inhibitor of Apoptosis Proteins Limit RIP3 Kinase-Dependent Interleukin-1 Activation
Open accessAbstract
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.
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“Importantly, multiple components of the molecular machinery for necroptosis—including ZBP1, RIPK3, MLKL, and TNFR1 (mainly via NF-κB)—impinge on the control of the so-called “inflammasome”, a supramolecular platform for the activation of CASP1 and consequent secretion of mature interleukin 1 beta (IL1B; best known as IL-1β) and IL18 [524–529].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [526]
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Metadata
- Authors
- Vince, J. E., Wong, W. W.-L., Gentle, I., 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.
- Affiliations
- University of Lausanne (CH)
- The University of Melbourne (AU)
- University of Freiburg (DE)
- Corresponding author
- Vince, James E.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 36
- Issue
- 2
- Pages
- 215-227
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2087968540
- Cited by
- 491
- References
- 62
- Citations by year
- 2026: 9 · 2025: 22 · 2024: 22 · 2023: 22 · 2022: 33 · 2021: 28 · 2020: 37 · 2019: 28 · 2018: 40 · 2017: 33 · 2016: 41 · 2015: 43 · 2014: 73 · 2013: 38 · 2012: 20
- FWCI
- 22.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 532 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Australian Government
- State Government of Victoria
- Deutsche Krebshilfe
- National Health and Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- inhibitor of apoptosis proteins, caspase-8, NLRP3 inflammasome, caspase-1, IAP antagonists, cIAP1, cIAP2, XIAP, ripoptosome, reactive oxygen species, macrophages, Toll-like receptors, inflammatory cytokines
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Baculoviral IAP Repeat-Containing 3 Protein, Animals, Carrier Proteins, Macrophages, Apoptosis, Reactive Oxygen Species, Mice, Knockout, Molecular Mimicry, Caspase 1, Mitochondrial Proteins, Ubiquitin-Protein Ligases, Apoptosis Regulatory Proteins, Inhibitor of Apoptosis Proteins, Mice, X-Linked Inhibitor of Apoptosis Protein, Receptor-Interacting Protein Serine-Threonine Kinases, Interleukin-1beta, Inflammasomes
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