{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:07:55Z","timestamp":1791497275771,"version":"4.3.4"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2012,7,1]],"date-time":"2012-07-01T00:00:00Z","timestamp":1341100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Expression of IL-33 is elevated in patients with pulmonary diseases, and full-length (not proteolytically processed) IL-33 is the predominant form in the lungs in health and disease. To determine whether activation of IL-33 is needed for functional effects, activities of full-length mouse and mature mouse (mm) forms of IL-33 were compared in vivo. Replication-deficient adenoviral constructs were used for gene delivery. Both isoforms caused pulmonary infiltration of lymphocytes and neutrophils, whereas mmIL-33 also caused pulmonary eosinophilia and goblet cell hyperplasia and increased expression of IL-4, IL-5, IL-13, IL-17, MCP-1, and KC. The different effects were not associated with differential release from IL-33\u2013producing cells or by differences in subcellular distributions of IL-33 isoforms. Germline deficiency of the cell surface receptor chain ST2 abrogated the mmIL-33\u2013induced Th2-associated effects (pulmonary eosinophilia, goblet cell hyperplasia, and increased IL-4 and IL-5), yet the lymphocytic infiltration induced by full-length mouse IL-33 or mmIL-33 was not fully abrogated by the absence of ST2. The similar effects of IL-33 isoforms were associated with comparable regulation of gene expression, notably matrix metalloproteinases 3, 10, and 13. Thus, full-length IL-33 is functionally active in vivo in an ST2-independent fashion, and its effects are partially different from those of mature IL-33. The different effects of these isoforms, particularly the pro-Th2 effects of mature IL-33, are due to differential utilization of the IL-33R chain ST2, whereas their similar effects result from regulation of gene expression.<\/jats:p>","DOI":"10.4049\/jimmunol.1200259","type":"journal-article","created":{"date-parts":[[2012,5,26]],"date-time":"2012-05-26T00:30:56Z","timestamp":1337992256000},"page":"403-410","source":"Crossref","is-referenced-by-count":99,"title":["Full-Length IL-33 Promotes Inflammation but not Th2 Response In Vivo in an ST2-Independent Fashion"],"prefix":"10.1093","volume":"189","author":[{"given":"Irina G","family":"Luzina","sequence":"first","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine , Baltimore, MD 21201"},{"name":"Baltimore Veterans Affairs Medical Center , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward M","family":"Pickering","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Kopach","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip H","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Lockatell","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevins W","family":"Todd","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine , Baltimore, MD 21201"},{"name":"Baltimore Veterans Affairs Medical Center , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C","family":"Papadimitriou","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N J","family":"McKenzie","sequence":"additional","affiliation":[{"name":"Medical Research Council Laboratory of Molecular Biology , Cambridge, CB2 0QH,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei P","family":"Atamas","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine , Baltimore, MD 21201"},{"name":"Baltimore Veterans Affairs Medical Center , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,7,1]]},"reference":[{"key":"2025032409162282100_r1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/j.1600-065X.2008.00624.x","article-title":"IL-1, IL-18, and IL-33 families of cytokines","volume":"223","author":"Arend","year":"2008","journal-title":"Immunol. Rev."},{"key":"2025032409162282100_r2","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nri2691","article-title":"The IL-1 family: regulators of immunity","volume":"10","author":"Sims","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"2025032409162282100_r3","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nri2692","article-title":"Disease-associated functions of IL-33: the new kid in the IL-1 family","volume":"10","author":"Liew","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"2025032409162282100_r4","doi-asserted-by":"crossref","first-page":"i43","DOI":"10.1136\/ard.2009.120113","article-title":"Role of interleukin 33 in human immunopathology","volume":"69","author":"Murphy","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"2025032409162282100_r5","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1073\/pnas.0606854104","article-title":"IL-33, the IL-1\u2013like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo","volume":"104","author":"Carriere","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032409162282100_r6","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.immuni.2005.09.015","article-title":"IL-33, an interleukin-1\u2013like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines","volume":"23","author":"Schmitz","year":"2005","journal-title":"Immunity"},{"key":"2025032409162282100_r7","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1002\/1521-4141(2002010)32:10<2979::AID-IMMU2979>3.0.CO;2-5","article-title":"Activated, but not resting human Th2 cells, in contrast to Th1 and T regulatory cells, produce soluble ST2 and express low levels of ST2L at the cell surface","volume":"32","author":"L\u00e9cart","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"2025032409162282100_r8","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.bbrc.2009.07.018","article-title":"Mature interleukin-33 is produced by calpain-mediated cleavage in vivo","volume":"387","author":"Hayakawa","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025032409162282100_r9","doi-asserted-by":"crossref","first-page":"7890","DOI":"10.4049\/jimmunol.0802449","article-title":"Caspase-1, caspase-8, and calpain are dispensable for IL-33 release by macrophages","volume":"183","author":"Ohno","year":"2009","journal-title":"J. Immunol."},{"key":"2025032409162282100_r10","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1016\/j.bbrc.2009.12.107","article-title":"Caspase 3 inactivates biologically active full length interleukin-33 as a classical cytokine but does not prohibit nuclear translocation","volume":"391","author":"Ali","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025032409162282100_r11","doi-asserted-by":"crossref","first-page":"19420","DOI":"10.1074\/jbc.M901744200","article-title":"Interleukin-33 is biologically active independently of caspase-1 cleavage","volume":"284","author":"Talabot-Ayer","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2025032409162282100_r12","doi-asserted-by":"crossref","first-page":"9021","DOI":"10.1073\/pnas.0812690106","article-title":"The IL-1\u2013like cytokine IL-33 is inactivated after maturation by caspase-1","volume":"106","author":"Cayrol","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032409162282100_r13","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.immuni.2009.05.007","article-title":"Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases","volume":"31","author":"L\u00fcthi","year":"2009","journal-title":"Immunity"},{"key":"2025032409162282100_r14","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.imlet.2010.04.005","article-title":"Over-expression of IL-33 leads to spontaneous pulmonary inflammation in mIL-33 transgenic mice","volume":"131","author":"Zhiguang","year":"2010","journal-title":"Immunol. Lett."},{"key":"2025032409162282100_r15","doi-asserted-by":"crossref","first-page":"5094","DOI":"10.4049\/jimmunol.0802387","article-title":"Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells","volume":"183","author":"Pr\u00e9fontaine","year":"2009","journal-title":"J. Immunol."},{"key":"2025032409162282100_r16","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1159\/000327259","article-title":"Expression and effects of IL-33 and ST2 in allergic bronchial asthma: IL-33 induces eotaxin production in lung fibroblasts","volume":"155","author":"Kurokawa","year":"2011","journal-title":"Int. Arch. Allergy Immunol."},{"key":"2025032409162282100_r17","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1165\/rcmb.2010-0516OC","article-title":"Infection with influenza virus induces IL-33 in murine lungs","volume":"45","author":"Le Goffic","year":"2011","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025032409162282100_r18","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s10067-011-1686-5","article-title":"Serum IL-33 levels are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis","volume":"30","author":"Yanaba","year":"2011","journal-title":"Clin. Rheumatol."},{"key":"2025032409162282100_r19","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1164\/ajrccm.164.2.2008120","article-title":"Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation","volume":"164","author":"Oshikawa","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025032409162282100_r20","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1378\/chest.124.4.1206","article-title":"The increase in serum soluble ST2 protein upon acute exacerbation of idiopathic pulmonary fibrosis","volume":"124","author":"Tajima","year":"2003","journal-title":"Chest"},{"key":"2025032409162282100_r21","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1002\/art.21950","article-title":"Induction of prolonged infiltration of T lymphocytes and transient T lymphocyte-dependent collagen deposition in mouse lungs following adenoviral gene transfer of CCL18","volume":"54","author":"Luzina","year":"2006","journal-title":"Arthritis Rheum."},{"key":"2025032409162282100_r22","doi-asserted-by":"crossref","first-page":"428","DOI":"10.2353\/ajpath.2007.061167","article-title":"Complex regulation of pulmonary inflammation and fibrosis by CCL18","volume":"171","author":"Pochetuhen","year":"2007","journal-title":"Am. J. Pathol."},{"key":"2025032409162282100_r23","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1002\/art.24435","article-title":"Regulation of pulmonary inflammation and fibrosis through expression of integrins \u03b1V\u03b23 and \u03b1V\u03b25 on pulmonary T lymphocytes","volume":"60","author":"Luzina","year":"2009","journal-title":"Arthritis Rheum."},{"key":"2025032409162282100_r24","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1111\/j.1365-2567.2010.03393.x","article-title":"Splice isoforms of human interleukin-4 are functionally active in mice in vivo","volume":"132","author":"Luzina","year":"2011","journal-title":"Immunology"},{"key":"2025032409162282100_r25","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1189\/jlb.0510271","article-title":"Alternatively spliced variants of interleukin-4 promote inflammation differentially","volume":"89","author":"Luzina","year":"2011","journal-title":"J. Leukoc. Biol."},{"key":"2025032409162282100_r26","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1182\/blood.V78.3.616.616","article-title":"Cloning and expression of murine interleukin-1 receptor antagonist in macrophages stimulated by colony-stimulating factor 1","volume":"78","author":"Matsushime","year":"1991","journal-title":"Blood"},{"key":"2025032409162282100_r27","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1165\/rcmb.2006-0033OC","article-title":"PKC\u03b1 mediates CCL18-stimulated collagen production in pulmonary fibroblasts","volume":"35","author":"Luzina","year":"2006","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025032409162282100_r28","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1002\/jcp.20452","article-title":"CCL18-stimulated upregulation of collagen production in lung fibroblasts requires Sp1 signaling and basal Smad3 activity","volume":"206","author":"Luzina","year":"2006","journal-title":"J. Cell. Physiol."},{"key":"2025032409162282100_r29","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1084\/jem.191.6.1069","article-title":"T1\/ST2-deficient mice demonstrate the importance of T1\/ST2 in developing primary T helper cell type 2 responses","volume":"191","author":"Townsend","year":"2000","journal-title":"J. Exp. Med."},{"key":"2025032409162282100_r30","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.1002\/eji.200737547","article-title":"IL-33 is a chemoattractant for human Th2 cells","volume":"37","author":"Komai-Koma","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"2025032409162282100_r31","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/intimm\/dxr006","article-title":"Endogenous IL-33 enhances Th2 cytokine production and T-cell responses during allergic airway inflammation","volume":"23","author":"Louten","year":"2011","journal-title":"Int. Immunol."},{"key":"2025032409162282100_r32","doi-asserted-by":"crossref","first-page":"724","DOI":"10.4049\/jimmunol.167.2.724","article-title":"Enforced expression of GATA-3 in transgenic mice inhibits Th1 differentiation and induces the formation of a T1\/ST2-expressing Th2-committed T cell compartment in vivo","volume":"167","author":"Nawijn","year":"2001","journal-title":"J. Immunol."},{"key":"2025032409162282100_r33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.bbaexp.2005.01.012","article-title":"T-helper type 2 cell-specific expression of the ST2 gene is regulated by transcription factor GATA-3","volume":"1728","author":"Hayakawa","year":"2005","journal-title":"Biochim. Biophys. Acta"},{"key":"2025032409162282100_r34","doi-asserted-by":"crossref","first-page":"6930","DOI":"10.1073\/pnas.95.12.6930","article-title":"T1\/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function","volume":"95","author":"L\u00f6hning","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032409162282100_r35","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.4049\/jimmunol.166.5.3143","article-title":"Regulation and function of T1\/ST2 expression on CD4+ T cells: induction of type 2 cytokine production by T1\/ST2 cross-linking","volume":"166","author":"Meisel","year":"2001","journal-title":"J. Immunol."},{"key":"2025032409162282100_r36","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.bbrc.2009.06.008","article-title":"Anti\u2013IL-33 antibody treatment inhibits airway inflammation in a murine model of allergic asthma","volume":"386","author":"Liu","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025032409162282100_r37","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1084\/jem.190.7.895","article-title":"Crucial role of the interleukin 1 receptor family member T1\/ST2 in T helper cell type 2-mediated lung mucosal immune responses","volume":"190","author":"Coyle","year":"1999","journal-title":"J. Exp. Med."},{"key":"2025032409162282100_r38","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1084\/jem.193.7.785","article-title":"Inhibition of T1\/ST2 during respiratory syncytial virus infection prevents T helper cell type 2 (Th2)- but not Th1-driven immunopathology","volume":"193","author":"Walzl","year":"2001","journal-title":"J. Exp. Med."},{"key":"2025032409162282100_r39","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1002\/eji.201141629","article-title":"IL-33 synergizes with TCR and IL-12 signaling to promote the effector function of CD8+ T cells","volume":"41","author":"Yang","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"2025032409162282100_r40","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/1471-2172-11-52","article-title":"Interleukin-33 contributes to both M1 and M2 chemokine marker expression in human macrophages","volume":"11","author":"Joshi","year":"2010","journal-title":"BMC Immunol."},{"key":"2025032409162282100_r41","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1093\/intimm\/dxn060","article-title":"IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells","volume":"20","author":"Smithgall","year":"2008","journal-title":"Int. Immunol."},{"key":"2025032409162282100_r42","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1073\/pnas.0712116105","article-title":"IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice","volume":"105","author":"Verri","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032409162282100_r43","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.4049\/jimmunol.1003080","article-title":"The dual function cytokine IL-33 interacts with the transcription factor NF-\u03baB to dampen NF-\u03baB\u2013stimulated gene transcription","volume":"187","author":"Ali","year":"2011","journal-title":"J. Immunol."},{"key":"2025032409162282100_r44","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1165\/ajrcmb.24.5.4160","article-title":"Role of stromelysin 1 and gelatinase B in experimental acute lung injury","volume":"24","author":"Warner","year":"2001","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025032409162282100_r45","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.yexmp.2007.04.003","article-title":"Matrix metalloproteinase-3 (stromelysin-1) in acute inflammatory tissue injury","volume":"83","author":"Nerusu","year":"2007","journal-title":"Exp. Mol. Pathol."},{"key":"2025032409162282100_r46","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1164\/rccm.200812-1902OC","article-title":"Differential expression of tissue repair genes in the pathogenesis of chronic obstructive pulmonary disease","volume":"181","author":"Gosselink","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025032409162282100_r47","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.ijrobp.2009.12.043","article-title":"Loss of matrix metalloproteinase-13 attenuates murine radiation-induced pulmonary fibrosis","volume":"77","author":"Flechsig","year":"2010","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"2025032409162282100_r48","first-page":"439","article-title":"Interactions of adenovirus vectors with blood: implications for intravascular gene therapy applications","volume":"10","author":"Parker","year":"2008","journal-title":"Curr. Opin. Mol. Ther."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/189\/1\/403\/61726081\/1200259.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/189\/1\/403\/61726081\/1200259.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T00:02:54Z","timestamp":1743033774000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/189\/1\/403\/7994806"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,7,1]]},"references-count":48,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2012,7,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1200259","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.717959565.793462822","asserted-by":"object"}]},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,7]]},"published":{"date-parts":[[2012,7,1]]}}}