IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G.
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-33(1-270) and generate mature forms IL-33(95-270), IL-33(99-270), and IL-33(109-270). 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.
Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse,  France.
Emma
E
Lefrançais
Stephane
S
Roga
Violette
V
Gautier
Anne
A
Gonzalez-de-Peredo
Bernard
B
Monsarrat
Jean-Philippe
JP
Girard
Corinne
C
Cayrol
D055371:Acute Lung Injury / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D056649:Cathepsin G / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D019272:Leukocyte Elastase / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism; D011499:Protein Processing, Post-Translational
C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins; D056649:Cathepsin G; D019272:Leukocyte Elastase