{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T14:18:59Z","timestamp":1773238739724,"version":"3.50.1"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[1999,3,1]],"date-time":"1999-03-01T00:00:00Z","timestamp":920246400000},"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":[[1999,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The formation of multinucleated giant cells (MGCs) in an in vivo model of pulmonary inflammation was investigated to determine whether these cells are the result of a dominant T helper (Th) 1 or Th2 cytokine environment. We report that knockout (KO) mice with a disrupted interleukin (IL)-12 p40 gene exposed to the helminth Schistosoma mansoni had abundant and very large MGCs (&amp;gt; 50 \u03bcm) in their lungs concurrent with extensive eosinophilia and a population of large macrophages. Many of the MGCs and macrophages appeared to have phagocytosed eosinophils as part of a clearance process. The KO mice also had a strongly polarized Th2 immune response as judged by elevated levels in the lungs of messenger RNA (mRNA) transcripts for IL-4, IL-5, IL-6, and IL-13, but decreased levels of mRNA for interferon-\u03b3 (IFN-\u03b3) and tumor necrosis factor-\u03b1 (TNF-\u03b1). In addition, cells recovered by bronchoalveolar lavage from the airways of these mice secreted a Th2-biased profile of cytokines upon restimulation in vitro with parasite antigen. In contrast, wild-type C57BL\/6 or KO mice treated with recombinant IL-12 had a polarized Th1 phenotype with elevated levels of IFN-\u03b3 and TNF-\u03b1 mRNA in the lungs, and an airway cell population that secreted abundant IFN-\u03b3. Very few MGCs were detected in these mice, and there was an absence of pulmonary eosinophilia. We conclude that the formation of MGCs in our model is promoted in the absence of IL-12 and is linked instead to the abundance of Th2 cytokines, notably IL-4 and IL-13.<\/jats:p>","DOI":"10.1165\/ajrcmb.20.3.3317","type":"journal-article","created":{"date-parts":[[2013,4,3]],"date-time":"2013-04-03T21:53:09Z","timestamp":1365025989000},"page":"371-378","source":"Crossref","is-referenced-by-count":11,"title":["Formation of Multinucleated Giant Cells in the Mouse Lung Is Promoted in the Absence of Interleukin-12"],"prefix":"10.1093","volume":"20","author":[{"given":"Sonia","family":"Anderson","sequence":"first","affiliation":[{"name":"Department of Biology, The University of York, York, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia L.","family":"Shires","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of York, York, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Alan Wilson","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of York, York, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian P.","family":"Mountford","sequence":"additional","affiliation":[{"name":"Department of Biology, The University of York, York, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[1999,3,1]]},"reference":[{"key":"2026030700135295900_B1","doi-asserted-by":"crossref","first-page":"585","DOI":"10.3109\/01913129609016363","article-title":"Giant cell pneumonia: light microscopy, immunohistochemical, and ultrastructural study of an autopsy case.","volume":"20","author":"Rahman","year":"1996","journal-title":"Ultrastruct. Pathol."},{"key":"2026030700135295900_B2","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1128\/iai.65.2.373-379.1997","article-title":"Role of gamma interferon in the host immune and inflammatory responses to Pneumocystis carinii infection.","volume":"65","author":"Garvy","year":"1997","journal-title":"Infect. Immun."},{"key":"2026030700135295900_B3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1365-3024.1985.tb00475.x","article-title":"Multinucleate giant cells in murine and rat lungs during Nippo-strongylus brasiliensis infections: a study of the kinetics of the response in vivo, cytochemistry, IgG- and C3-mediated function.","volume":"7","author":"Egwang","year":"1985","journal-title":"Parasite Immunol."},{"key":"2026030700135295900_B4","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.1365-3024.1986.tb01038.x","article-title":"The role of pulmonary cellular reactions in the resistance of vaccinated mice to Schistosoma mansoni.","volume":"8","author":"Crabtree","year":"1986","journal-title":"Parasite Immunol."},{"key":"2026030700135295900_B5","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1159\/000195218","article-title":"Multinuclear giant cells in bronchoalveolar lavage in interstitial lung diseases.","volume":"51","author":"Agusti","year":"1987","journal-title":"Respiration"},{"key":"2026030700135295900_B6","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1002\/jlb.59.4.534","article-title":"Alveolar macrophage kinetics and multinucleated giant cell formation after lung injury.","volume":"59","author":"Priediitis","year":"1996","journal-title":"J. Leukoc. Biol."},{"key":"2026030700135295900_B7","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/S0167-5699(97)01148-1","article-title":"The biological relevance of polykaryons in the immune response.","volume":"11","author":"Fais","year":"1997","journal-title":"Immunol. Today"},{"key":"2026030700135295900_B8","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/path.1711260302","article-title":"Multinucleated giant cells.","volume":"126","author":"Chambers","year":"1978","journal-title":"J. Pathol."},{"key":"2026030700135295900_B9","first-page":"232","article-title":"Multinucleated giant cells generated in vitro: terminally differentiated macrophages with down-regulated cfms expression.","volume":"130","author":"Kreipe","year":"1988","journal-title":"Am. J. Pathol."},{"key":"2026030700135295900_B10","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1002\/eji.1830200807","article-title":"Cytokine-induced generation of multinucleated giant cells in vitro requires interferon-\u03b3 and expression of LFA-1.","volume":"20","author":"Most","year":"1990","journal-title":"Eur. J. Immunol."},{"key":"2026030700135295900_B11","first-page":"737","article-title":"Multinucleated giant cell generation induced by interferon-gamma: changes in the expression and distribution of the ICAM-1 during macrophage fusion and multinucleated giant cell formation.","volume":"71","author":"Fais","year":"1994","journal-title":"Lab. Invest."},{"key":"2026030700135295900_B12","first-page":"1487","article-title":"Interleukin-4 induces foreign body giant cells from human monocytes\/macrophages.","volume":"147","author":"McNally","year":"1995","journal-title":"Am. J. Pathol."},{"key":"2026030700135295900_B13","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1084\/jem.167.2.598","article-title":"IL-4 induces cultured monocytes\/macrophages to form giant multinucleated cells.","volume":"167","author":"McInnes","year":"1988","journal-title":"J. Exp. Med."},{"key":"2026030700135295900_B14","doi-asserted-by":"crossref","first-page":"7151","DOI":"10.4049\/jimmunol.151.12.7151","article-title":"Modulation of murine macrophage function by IL-13.","volume":"151","author":"Doherty","year":"1993","journal-title":"J. Immunol."},{"key":"2026030700135295900_B15","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1146\/annurev.iy.13.040195.001343","article-title":"Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity.","volume":"13","author":"Trinchieri","year":"1995","journal-title":"Annu. Rev. Immunol."},{"key":"2026030700135295900_B16","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/0923-2494(96)83011-2","article-title":"Interleukin 12: a proinflammmatory cytokine with immunoregulatory functions.","volume":"146","author":"Trinchieri","year":"1995","journal-title":"Res. Immunol."},{"key":"2026030700135295900_B17","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S1074-7613(00)80413-6","article-title":"IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses.","volume":"4","author":"Magram","year":"1996","journal-title":"Immunity"},{"key":"2026030700135295900_B18","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1017\/S0031182000066701","article-title":"Antigen localisation and the induction of resistance in mice vaccinated with irradiated cercariae of Schistosoma mansoni.","volume":"97","author":"Mountford","year":"1988","journal-title":"Parasitology"},{"key":"2026030700135295900_B19","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0065-308X(08)60048-2","article-title":"The radiation-attenuated vaccine against schistosomes in animal models: paradigm for a human vaccine.","volume":"39","author":"Coulson","year":"1997","journal-title":"Adv. Parasitol."},{"key":"2026030700135295900_B20","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.4049\/jimmunol.148.5.1512","article-title":"T cell-derived cytokines associated with pulmonary immune mechanisms in mice vaccinated with irradiated cercariae of Schistosoma mansoni.","volume":"148","author":"Smythies","year":"1992","journal-title":"J. Immunol."},{"key":"2026030700135295900_B21","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1046\/j.1365-3024.1996.d01-115.x","article-title":"Kinetics and mechanism of effector focus formation in the lungs of mice vaccinated with irradiated cercariae of Schistosoma mansoni.","volume":"18","author":"Smythies","year":"1996","journal-title":"Parasite Immunol."},{"key":"2026030700135295900_B22","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1128\/iai.63.5.1980-1986.1995","article-title":"Antigens derived from lung-stage larvae of Schistosoma mansoni are efficient stimulators of proliferation and gamma interferon secretion by lymphocytes from mice vaccinated with attenuated larvae.","volume":"63","author":"Mountford","year":"1995","journal-title":"Infect. Immun."},{"key":"2026030700135295900_B23","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1046\/j.1365-2567.1996.465550.x","article-title":"Impaired immunity and altered pulmonary responses in mice with a disrupted interferon-\u03b3 receptor gene exposed to the irradiated Schistosoma mansoni vaccine.","volume":"87","author":"Wilson","year":"1996","journal-title":"Immunology"},{"key":"2026030700135295900_B24","doi-asserted-by":"crossref","first-page":"554","DOI":"10.4049\/jimmunol.147.2.554","article-title":"Analysis of cytokine gene expression during fetal thymic ontogeny using the polymerase chain reaction.","volume":"147","author":"Montgomery","year":"1991","journal-title":"J. Immunol."},{"key":"2026030700135295900_B25","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.4049\/jimmunol.151.3.1430","article-title":"Analysis of cytokine mRNA expression during primary granuloma formation induced by eggs of Schistosoma mansoni.","volume":"151","author":"Wynn","year":"1993","journal-title":"J. Immunol."},{"key":"2026030700135295900_B26","doi-asserted-by":"crossref","first-page":"285","DOI":"10.4049\/jimmunol.155.1.285","article-title":"Thapsigargin and cyclopiazonic acid initiate rapid and dramatic increases in IL-6 mRNA expression and IL-6 secretion in murine peritoneal macrophages.","volume":"155","author":"Bost","year":"1995","journal-title":"J. Immunol."},{"key":"2026030700135295900_B27","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/0022-1759(93)90386-L","article-title":"Detection of in vivo expression of interleukin-10 using a semi-quantitative polymerase chain reaction method in Schistosoma mansoni infected mice.","volume":"162","author":"Murphy","year":"1993","journal-title":"J. Immunol. Meth."},{"key":"2026030700135295900_B28","doi-asserted-by":"crossref","first-page":"365","DOI":"10.2307\/3282668","article-title":"In situ pulmonary responses of T cell and macrophage subpopulations to a challenge infection in mice vaccinated with irradiated cercariae of Schistosoma mansoni.","volume":"76","author":"Kambara","year":"1990","journal-title":"J. Parasitol."},{"key":"2026030700135295900_B29","doi-asserted-by":"crossref","first-page":"3654","DOI":"10.4049\/jimmunol.149.11.3654","article-title":"Monoclonal antibody to interferon-gamma modifies pulmonary inflammatory responses and abrogates immunity to Schistosoma mansoni in mice vaccinated with attenuated cercariae.","volume":"149","author":"Smythies","year":"1992","journal-title":"J. Immunol."},{"key":"2026030700135295900_B30","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.4049\/jimmunol.158.6.2898","article-title":"IL-13 protects mice from lipopolysaccharide-induced lethal endotoxemia.","volume":"158","author":"Muchamuel","year":"1997","journal-title":"J. Immunol."},{"key":"2026030700135295900_B31","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1002\/eji.1830240630","article-title":"IL-13 alters the activation state of murine macrophages in vitro: comparison with IL-4 and IFN-\u03b3.","volume":"24","author":"Doyle","year":"1994","journal-title":"Eur. J. Immunol."},{"key":"2026030700135295900_B32","doi-asserted-by":"crossref","first-page":"3385","DOI":"10.4049\/jimmunol.158.7.3385","article-title":"Interleukin 13 induces human monocyte\/macrophage fusion and macrophage mannose receptor expression.","volume":"158","author":"De Fife","year":"1997","journal-title":"J. Immunol."},{"key":"2026030700135295900_B33","doi-asserted-by":"crossref","first-page":"4226","DOI":"10.4049\/jimmunol.144.11.4226","article-title":"IL-6 stimulates osteoclast-like multinucleated cell formation in long term human marrow cultures by inducing IL-1 release.","volume":"144","author":"Kurihara","year":"1990","journal-title":"J. Immunol."},{"key":"2026030700135295900_B34","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1165\/ajrcmb\/6.1.57","article-title":"Induction of multinucleated giant cell formation from in vitro culture of human monocytes with interleukin-3 and interferon-gamma: comparison with other stimulating factors.","volume":"6","author":"Enelow","year":"1992","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2026030700135295900_B35","doi-asserted-by":"crossref","first-page":"3002","DOI":"10.4049\/jimmunol.150.7.3002","article-title":"Differential regulation of formation of multinucleated giant cells from Concanavalin A-stimulated human blood monocytes by IFN-\u03b3 and IL-4.","volume":"150","author":"Takashima","year":"1993","journal-title":"J. Immunol."},{"key":"2026030700135295900_B36","doi-asserted-by":"crossref","first-page":"900","DOI":"10.4049\/jimmunol.148.3.900","article-title":"Role of IL-4 and IFN-\u03b3 in Schistosoma mansoni egg-induced hypersensitivity granuloma formation.","volume":"148","author":"Chensue","year":"1992","journal-title":"J. Immunol."},{"key":"2026030700135295900_B37","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1002\/(SICI)1521-4141(199809)28:09<2827::AID-IMMU2827>3.0.CO;2-K","article-title":"In the absence of interleukin-12, the induction of Th1-mediated protective immunity by the attenuated schistosome vaccine is impaired, revealing an alternative pathway with Th2-type characteristics.","volume":"9","author":"Anderson","year":"1998","journal-title":"Eur. J. Immunol."}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/20\/3\/371\/67193943\/ajrcmb_20_3_371.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/20\/3\/371\/67193943\/ajrcmb_20_3_371.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T05:24:21Z","timestamp":1772861061000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/20\/3\/371\/8503008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,3,1]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[1999,3,1]]},"published-print":{"date-parts":[[1999,3,1]]}},"URL":"https:\/\/doi.org\/10.1165\/ajrcmb.20.3.3317","relation":{},"ISSN":["1535-4989","1044-1549"],"issn-type":[{"value":"1535-4989","type":"electronic"},{"value":"1044-1549","type":"print"}],"subject":[],"published-other":{"date-parts":[[1999,3]]},"published":{"date-parts":[[1999,3,1]]}}}