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The histological pattern marks a critical step in the progression from chronic gastritis to gastric cancer, yet underlying mechanism(s) of inflammation\u2010induced cell death of gastric epithelial cells are poorly understood. We investigated direct effects of a type 1 cytokine associated with autoimmunity and infection, interferon\u2010\u03b3 (IFN\u2010\u03b3), on gastric epithelial cells. IFN\u2010\u03b3 was applied to three\u2010dimensional organoid cultures of gastric epithelial cells derived from gastric corpus gland (gastroids) of control and IFN\u2010\u03b3 receptor\u2010deficient mice. Gastroids were also treated with supernatants from activated immune cells isolated from a mouse model of autoimmune\u2010mediated atrophic gastritis (TxA23) with and without IFN\u2010\u03b3 expression. Finally, histopathological analysis of atrophy and metaplasia severity was performed in TxA23 mice and compared to TxA23 \u00d7 <jats:italic>Ifng<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Gastric epithelial cells in gastroid cultures expressed IFN\u2010\u03b3 receptor in the basolateral membrane, and gastroids died when treated with IFN\u2010\u03b3 in an IFN\u2010\u03b3 receptor\u2010dependent manner. Supernatants from immune cells containing high levels of IFN\u2010\u03b3 were highly toxic to gastroids, and toxicity was tempered when IFN\u2010\u03b3 was either neutralized using a monoclonal antibody or when supernatants from <jats:italic>Ifng<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mouse immune cells were used. Finally, TxA23 \u00d7 <jats:italic>Ifng<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice showed near\u2010complete abrogation of pre\u2010cancerous histopathological atrophy and metaplasia versus IFN\u2010\u03b3\u2010sufficient controls. We identify IFN\u2010\u03b3 as a critical promoter of parietal cell atrophy with metaplasia during the progression of gastritis to gastric atrophy and metaplasia. Copyright \u00a9 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5214","type":"journal-article","created":{"date-parts":[[2018,12,4]],"date-time":"2018-12-04T02:05:15Z","timestamp":1543889115000},"page":"513-523","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Interferon\u2010\u03b3 directly induces gastric epithelial cell death and is required for progression to metaplasia"],"prefix":"10.1002","volume":"247","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0665-7567","authenticated-orcid":false,"given":"Luciana H","family":"Osaki","sequence":"first","affiliation":[{"name":"Department of Medicine Washington University School of Medicine  Saint Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5010-4970","authenticated-orcid":false,"given":"Kevin A","family":"Bockerstett","sequence":"additional","affiliation":[{"name":"Department of 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