{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:26:24Z","timestamp":1791332784215,"version":"4.3.1"},"reference-count":59,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,6,10]],"date-time":"2016-06-10T00:00:00Z","timestamp":1465516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HHSN272201000005I"],"award-info":[{"award-number":["HHSN272201000005I"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2016,7]]},"abstract":"Abstract<\/jats:title>\n \n Persistent or dysregulated\n IL<\/jats:styled-content>\n \u201013 responses are key drivers of fibrosis in multiple organ systems, and this identifies this cytokine as an important therapeutic target. Nevertheless, the mechanisms by which\n IL<\/jats:styled-content>\n \u201013 blockade leads to the amelioration of fibrosis remain unclear. Because\n IFN<\/jats:styled-content>\n \u2010\u03b3 exhibits potent anti\u2010fibrotic activity, and\n IL\u20104R\u03b1<\/jats:styled-content>\n signalling antagonizes\n IFN<\/jats:styled-content>\n \u2010\u03b3 effector function, compensatory increases in\n IFN<\/jats:styled-content>\n \u2010\u03b3 activity following\n IL<\/jats:styled-content>\n \u201013\/\n IL\u20104R\u03b1<\/jats:styled-content>\n blockade might contribute to the reduction in fibrosis. To investigate the role of\n IFN<\/jats:styled-content>\n \u2010\u03b3, we developed novel\n IL<\/jats:styled-content>\n \u201013\n \u2212\/\u2212<\/jats:sup>\n \/\n IFN<\/jats:styled-content>\n \u2010\u03b3\n \u2212\/\u2212<\/jats:sup>\n double cytokine\u2010deficient mice and examined disease progression in models of type 2\u2010driven fibrosis. As predicted, we showed that fibrosis in the lung and liver are both highly dependent on\n IL<\/jats:styled-content>\n \u201013. We also observed increased\n IFN<\/jats:styled-content>\n \u2010\u03b3 production and inflammatory activity in the tissues of\n IL<\/jats:styled-content>\n \u201013\u2010deficient mice. Surprisingly, however, an even greater reduction in fibrosis was observed in\n IL<\/jats:styled-content>\n \u201013\/\n IFN<\/jats:styled-content>\n \u2010\u03b3 double deficient mice, most notably in the livers of mice chronically infected with\n Schistosoma mansoni<\/jats:italic>\n . The increased protection was associated with marked decreases in\n Tgfb1<\/jats:italic>\n ,\n Mmp12<\/jats:italic>\n , and\n Timp1<\/jats:italic>\n mRNA<\/jats:styled-content>\n expression in the tissues; reduced inflammation; and decreased expression of important pro\u2010inflammatory mediators such as\n TNF<\/jats:styled-content>\n \u2010\u03b1. Experiments conducted with neutralizing monoclonal antibodies to\n IL<\/jats:styled-content>\n \u201013 and\n IFN<\/jats:styled-content>\n \u2010\u03b3 validated the findings with the genetically deficient mice. Together, these studies demonstrate that the reduction in fibrosis observed when\n IL<\/jats:styled-content>\n \u201013 signalling is suppressed is not dependent on increased\n IFN<\/jats:styled-content>\n \u2010\u03b3 activity. Instead, by reducing compensatory increases in type 1\u2010associated inflammation, therapeutic strategies that block\n IFN<\/jats:styled-content>\n \u2010\u03b3 and\n IL<\/jats:styled-content>\n \u201013 activity simultaneously can confer greater protection from progressive fibrosis than\n IL<\/jats:styled-content>\n \u201013 blockade alone. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.\n <\/jats:p>","DOI":"10.1002\/path.4733","type":"journal-article","created":{"date-parts":[[2016,4,30]],"date-time":"2016-04-30T09:04:34Z","timestamp":1462007074000},"page":"344-354","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Enhanced protection from fibrosis and inflammation in the combined absence of IL\u201013 and\n IFN<\/scp>\n \u2010\u03b3"],"prefix":"10.1002","volume":"239","author":[{"given":"Thirumalai R","family":"Ramalingam","sequence":"first","affiliation":[{"name":"Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L","family":"Gieseck","sequence":"additional","affiliation":[{"name":"Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases Bethesda MD 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