{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T01:22:32Z","timestamp":1793409752359,"version":"4.5.0"},"reference-count":45,"publisher":"National Academy of Sciences","issue":"5","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,1,31]]},"abstract":"<jats:p>\n                    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-1\u03b2 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-1\u03b1 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\n                    <jats:sub>1\u2013270<\/jats:sub>\n                    and generate mature forms IL-33\n                    <jats:sub>95\u2013270<\/jats:sub>\n                    , IL-33\n                    <jats:sub>99\u2013270<\/jats:sub>\n                    , and IL-33\n                    <jats:sub>109\u2013270<\/jats:sub>\n                    . These forms are produced by activated human neutrophils ex vivo, are biologically active in vivo, and have a \u223c10-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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1115884109","type":"journal-article","created":{"date-parts":[[2012,1,18]],"date-time":"2012-01-18T00:37:35Z","timestamp":1326847055000},"page":"1673-1678","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":569,"title":["IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G"],"prefix":"10.1073","volume":"109","author":[{"given":"Emma","family":"Lefran\u00e7ais","sequence":"first","affiliation":[{"name":"Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Universit\u00e9 de Toulouse, Universit\u00e9 Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephane","family":"Roga","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Universit\u00e9 de Toulouse, Universit\u00e9 Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violette","family":"Gautier","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Universit\u00e9 de Toulouse, Universit\u00e9 Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Gonzalez-de-Peredo","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Universit\u00e9 de Toulouse, Universit\u00e9 Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Monsarrat","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Universit\u00e9 de Toulouse, Universit\u00e9 Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Philippe","family":"Girard","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Universit\u00e9 de Toulouse, Universit\u00e9 Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Cayrol","sequence":"additional","affiliation":[{"name":"Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France; Universit\u00e9 de Toulouse, Universit\u00e9 Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,1,17]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132612"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2691"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-07-273417"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.09.015"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63631-0"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0606854104"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/embor.2008.145"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2222.2009.03384.x"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2692"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.2332\/allergolint.10-RAI-0186"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0906312"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0801898105"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24305"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912678107"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30634"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0906988106"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08636"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08900"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1003988107"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2045"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2131"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1003059107"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0812690106"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.05.007"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M901744200"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.12.107"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003331"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature00858"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1603"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0306164"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0915018107"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102048"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1841"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)39328-7"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.11.6261"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24959"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.25006"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2010.04.007"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200503-343OC"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxr006"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.122655"},{"key":"e_1_3_3_42_2","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.4049\/jimmunol.158.4.1818","article-title":"Response to local inflammation of IL-1 beta-converting enzyme- deficient mice","volume":"158","author":"Fantuzzi G","year":"1997","unstructured":"G Fantuzzi, et al., Response to local inflammation of IL-1 beta-converting enzyme- deficient mice. 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