Suppression of Interleukin-33 Bioactivity through Proteolysis by Apoptotic Caspases
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Interleukin-33 (IL-33) is a member of the IL-1 family and is involved in polarization of T cells toward a T helper 2 (Th2) cell phenotype. IL-33 is thought to be activated via caspase-1-dependent proteolysis, similar to the proinflammatory cytokines IL-1 beta and IL-18, but this remains unproven. Here we showed that IL-33 was processed by caspases activated during apoptosis (caspase-3 and -7) but was not a physiological substrate for caspases associated with inflammation (caspase-1, -4, and -5). Furthermore, caspase-dependent processing of IL-33 was not required for ST2 receptor binding or ST2-dependent activation of the NF-kappaB transcription factor. Indeed, caspase-dependent proteolysis of IL-33 dramatically attenuated IL-33 bioactivity in vitro and in vivo. These data suggest that IL-33 does not require proteolysis for activation, but rather, that IL-33 bioactivity is diminished through caspase-dependent proteolysis within apoptotic cells. Thus, caspase-mediated proteolysis acts as a switch to dampen the proinflammatory properties of IL-33.
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Although it was initially thought that the IL-33 precursor was processed by caspase 1 to produce biologically active IL-33, it is now clear that its processing by the executioner caspases caspase 3 and caspase 7 during apoptosis inactivates IL-33.
“Although it was initially thought that the IL-33 precursor was processed by caspase 1 to produce biologically active IL-33, it is now clear that its processing by the executioner caspases caspase 3 and caspase 7 during apoptosis inactivates IL-33 (REFS 85,86).”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [85]
Extracellular IL-33 that is released during necrosis functions as an alarmin to alert cells, such as mast cells and other innate immune cells, to tissue damage.
“extracellular IL-33 that is released during necrosis also functions as an alarmin to alert cells, such as mast cells and other innate immune cells, to tissue damage85,86.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [85]
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Self-citation
- Authors
- Lüthi, A. U., Cullen, S. P., McNeela, E. A., Duriez, P. J., Afonina, I. S., Sheridan, C., Brumatti, G., Taylor, R. C., Kersse, K., Vandenabeele, P., Lavelle, E. C., & Martin, S. J.
- Affiliations
- Trinity College Dublin (IE)
- Vlaams Instituut voor Biotechnologie (BE)
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2009-07
- Volume
- 31
- Issue
- 1
- Pages
- 84-98
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2078489088
- Cited by
- 677
- References
- 24
- Citations by year
- 2026: 16 · 2025: 12 · 2024: 17 · 2023: 28 · 2022: 36 · 2021: 42 · 2020: 38 · 2019: 33 · 2018: 46 · 2017: 33 · 2016: 52 · 2015: 57 · 2014: 52 · 2013: 53 · 2012: 57
- FWCI
- 23.30
- 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, 1477 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)
- Arrow@dit (Dublin Institute of Technology) (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, cc-by-nc-sa)
- Funders
- Health Research Board (RP/2006/233)
- Science Foundation Ireland (PI1/B038)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- IL-33, caspase-3, caspase-7, apoptosis, ST2 receptor, NF-κB activation, IL-1 family cytokines, cytokine bioactivity, anti-inflammatory regulation
- MeSH terms
- Interleukin-33, Interleukin-1 Receptor-Like 1 Protein, Animals, Humans, Interleukins, Lymphocytes, Membrane Proteins, Mice, Inbred C57BL, NF-kappa B, Apoptosis, Receptors, Interleukin, Amino Acid Substitution, Caspase 1, Mice, Caspase 3, Caspase 7
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