The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1
Open accessAbstract
IL-33 is a chromatin-associated cytokine of the IL-1 family that has recently been linked to many diseases, including asthma, rheumatoid arthritis, atherosclerosis, and cardiovascular diseases. IL-33 signals through the IL-1 receptor-related protein ST2 and drives production of pro-inflammatory and T helper type 2-associated cytokines in mast cells, T helper type 2 lymphocytes, basophils, eosinophils, invariant natural killer T cells, and natural killer cells. It is currently believed that IL-33, like IL-1β and IL-18, requires processing by caspase-1 to a mature form (IL-33 112–270 ) for biological activity. Contrary to the current belief, we report here that full-length IL-33 1–270 is active and that processing by caspase-1 results in IL-33 inactivation, rather than activation. We show that full-length IL-33 1–270 binds and activates ST2, similarly to IL-33 112–270 , and that cleavage by caspase-1 does not occur at the site initially proposed (Ser 111 ), but rather after residue Asp 178 between the fourth and fifth predicted β-strands of the IL-1-like domain. Surprisingly, the caspase-1 cleavage site (DGVD 178 G) is similar to the consensus site of cleavage by caspase-3, and IL-33 is also a substrate for this apoptotic caspase. Interestingly, we found that full-length IL-33, which is constitutively expressed to high levels by endothelial cells in most normal human tissues, can be released in the extracellular space after endothelial cell damage or mechanical injury. We speculate that IL-33 may function, similarly to the prototypical alarmins HMGB1 and IL-1α, as an endogenous danger signal to alert cells of the innate immune system of tissue damage during trauma or infection.
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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 [86]
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 [86]
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- Authors
- Cayrol, C., & Girard, J.-P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Girard, Jean-Philippe
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-06-02
- Volume
- 106
- Issue
- 22
- Pages
- 9021-9026
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2690027
- OpenAlex
- W2069526125
- Cited by
- 707
- References
- 36
- Citations by year
- 2026: 17 · 2025: 19 · 2024: 24 · 2023: 30 · 2022: 38 · 2021: 33 · 2020: 36 · 2019: 31 · 2018: 50 · 2017: 41 · 2016: 50 · 2015: 59 · 2014: 56 · 2013: 60 · 2012: 54
- FWCI
- 23.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agence Nationale de la Recherche
- 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-1, caspase-3, ST2, IL-1 family cytokines, cytokine processing, cleavage site, alarmins, damage-associated molecular patterns, endothelial cells, tissue damage, innate immunity, Th2 cytokines
- MeSH terms
- Interleukin-33, Interleukin-1 Receptor-Like 1 Protein, Cell Line, DNA Mutational Analysis, Humans, Interleukin-1, Interleukins, Receptors, Cell Surface, Sequence Deletion, Protein Structure, Secondary, Protein Structure, Tertiary, Caspase 1, Endothelial Cells
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