IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G
- 17 January 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 109 (5), 1673-1678
- https://doi.org/10.1073/pnas.1115884109
Abstract
Interleukin-33 (IL-33) (NF-HEV) is a chromatin-associated nuclear cytokine from the IL-1 family, which has been linked to important diseases, including asthma, rheumatoid arthritis, ulcerative colitis, and cardiovascular diseases. IL-33 signals through the ST2 receptor and drives cytokine production in type 2 innate lymphoid cells (ILCs) (natural helper cells, nuocytes), T-helper (Th)2 lymphocytes, mast cells, basophils, eosinophils, invariant natural killer T (iNKT), and natural killer (NK) cells. We and others recently reported that, unlike IL-1β and IL-18, full-length IL-33 is biologically active independently of caspase-1 cleavage and that processing by caspases results in IL-33 inactivation. We suggested that IL-33, which is released upon cellular damage, may function as an endogenous danger signal or alarmin, similar to IL-1α or high-mobility group box 1 protein (HMGB1). Here, we investigated the possibility that IL-33 activity may be regulated by proteases released during inflammation. Using a combination of in vitro and in vivo approaches, we demonstrate that neutrophil serine proteases cathepsin G and elastase can cleave full-length human IL-331–270and generate mature forms IL-3395–270, IL-3399–270, and IL-33109–270. These forms are produced by activated human neutrophils ex vivo, are biologically active in vivo, and have a ∼10-fold higher activity than full-length IL-33 in cellular assays. Murine IL-33 is also cleaved by neutrophil cathepsin G and elastase, and both full-length and cleaved endogenous IL-33 could be detected in the bronchoalveolar lavage fluid in an in vivo model of acute lung injury associated with neutrophil infiltration. We propose that the inflammatory microenvironment may exacerbate disease-associated functions of IL-33 through the generation of highly active mature forms.Keywords
This publication has 46 references indexed in Scilit:
- Granzyme B-Dependent Proteolysis Acts as a Switch to Enhance the Proinflammatory Activity of IL-1αMolecular Cell, 2011
- Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunityNature Immunology, 2011
- A Large-Scale, Consortium-Based Genomewide Association Study of AsthmaNew England Journal of Medicine, 2010
- Nuocytes represent a new innate effector leukocyte that mediates type-2 immunityNature, 2010
- Inflammatory arthritis in caspase 1 gene–deficient mice: Contribution of proteinase 3 to caspase 1–independent production of bioactive interleukin‐1βArthritis & Rheumatism, 2009
- Caspase 1–independent activation of interleukin‐1β in neutrophil‐predominant inflammationArthritis & Rheumatism, 2009
- Molecular mimicry between IL‐33 and KSHV for attachment to chromatin through the H2A–H2B acidic pocketEMBO Reports, 2008
- IL-33 exacerbates antigen-induced arthritis by activating mast cellsProceedings of the National Academy of Sciences, 2008
- IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factorin vivoProceedings of the National Academy of Sciences, 2007
- Neutrophil serine proteases: specific regulators of inflammationNature Reviews Immunology, 2006