{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T23:17:07Z","timestamp":1790983027393,"version":"4.1.0"},"reference-count":55,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,6,1]]},"abstract":"<jats:p>IFN\u03b3 (interferon \u03b3), a cytokine typically secreted by infiltrating immune cells in insulitis in Type\u00a01 diabetes, is by itself not detrimental to \u03b2-cells, but, together with other cytokines, such as IL-1\u03b2 (interleukin 1\u03b2) and TNF\u03b1 (tumour necrosis factor \u03b1), or dsRNA (double-stranded RNA), it induces \u03b2-cell apoptosis. The complex gene and protein networks that are altered by the combination of cytokines clearly point towards synergisms between these agents. IFN\u03b3 acts mostly via JAK (Janus kinase) activation, with the transcription factors STAT-1 (signal transducer and activator of transcription-1) and IRF-1 (IFN\u03b3 regulatory factor-1) playing a central role in the downstream pathway. The study of mice with a disruption of these transcription factors has revealed a possible dual role for IFN\u03b3 in \u03b2-cell destruction by cytokines or dsRNA. We demonstrated that the absence of STAT-1 from \u03b2-cells completely protects against IFN\u03b3+IL-1\u03b2- and IFN\u03b3+dsRNA-mediated \u03b2-cell death in vitro, whereas absence of IRF-1 does not prevent cytokine-induced \u03b2-cell apoptosis. In vivo, a lack of the IRF-1 gene in pancreatic islets even promotes low-dose streptozotocin-induced diabetes, whereas lack of STAT-1 confers resistance against \u03b2-cell death following low-dose streptozotocin-induced diabetes. Additionally, IRF-1\u2212\/\u2212 islets are more sensitive to PNF (primary islet non-function) after transplantation in spontaneously diabetic NOD (non-obese diabetic) mice, whereas STAT-1\u2212\/\u2212 islets are fully protected. Moreover, proteomic analysis of \u03b2-cells exposed to IFN\u03b3 or IFN\u03b3+IL-1\u03b2 confirms that very different pathways are activated by IFN\u03b3 alone compared with the combination. We conclude that IFN\u03b3 may play a dual role in immune-induced \u03b2-cell destruction. Transcription factors drive this dual role, with STAT-1 driving \u03b2-cell destruction and IRF-1 possibly playing a role in up-regulation of protective pathways induced by IFN\u03b3.<\/jats:p>","DOI":"10.1042\/bst0360328","type":"journal-article","created":{"date-parts":[[2008,6,11]],"date-time":"2008-06-11T13:27:46Z","timestamp":1213190866000},"page":"328-333","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Cytokine signalling in the \u03b2-cell: a dual role for IFN\u03b3"],"prefix":"10.1042","volume":"36","author":[{"given":"Conny","family":"Gysemans","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Medicine and Endocrinology (LEGENDO), UZ Gasthuisberg O&N, Katholieke Universiteit Leuven, Herestraat 49, bus 902, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanne","family":"Callewaert","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Medicine and Endocrinology (LEGENDO), UZ Gasthuisberg O&N, Katholieke Universiteit Leuven, Herestraat 49, bus 902, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutgart","family":"Overbergh","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Medicine and Endocrinology (LEGENDO), UZ Gasthuisberg O&N, Katholieke Universiteit Leuven, Herestraat 49, bus 902, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Mathieu","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Medicine and Endocrinology (LEGENDO), UZ Gasthuisberg O&N, Katholieke Universiteit Leuven, Herestraat 49, bus 902, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2008,5,21]]},"reference":[{"key":"2021111720164524700_B1","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1097\/01.tp.0000191939.68451.d9","article-title":"A critical role for granzyme B, in addition to perforin and TNF-\u03b1, in alloreactive CTL-induced mouse pancreatic \u03b2-cell death","volume":"81","author":"Sutton","year":"2006","journal-title":"Transplantation"},{"key":"2021111720164524700_B2","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.2337\/db06-0109","article-title":"Cytotoxic T-cells from T-cell receptor transgenic NOD8.3 mice destroy \u03b2-cells via the perforin and Fas pathways","volume":"55","author":"Dudek","year":"2006","journal-title":"Diabetes"},{"key":"2021111720164524700_B3","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1093\/intimm\/dxl020","article-title":"Perforin and Fas induced by IFN-\u03b3 and TNF-\u03b1 mediate \u03b2-cell death by OT-I CTL","volume":"18","author":"McKenzie","year":"2006","journal-title":"Int. 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