{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T11:36:22Z","timestamp":1787830582810,"version":"build-2784847793"},"reference-count":67,"publisher":"The Endocrine Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2002,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Viral infections may trigger the autoimmune assault leading to type 1 diabetes mellitus. Double-stranded RNA (dsRNA) is produced by many viruses during their replicative cycle. The dsRNA, tested as synthetic poly(IC) (PIC), in synergism with the proinflammatory cytokines interferon-\u03b3 (IFN-\u03b3) and\/or IL-1\u03b2, results in nitric oxide production, Fas expression, \u03b2-cell dysfunction, and death. Activation of the transcription nuclear factor-\u03baB (NF-\u03baB) is required for PIC-induced inducible nitric oxide synthase expression in \u03b2-cells, and we hypothesized that this transcription factor may also participate in PIC-induced Fas expression and \u03b2-cell apoptosis. This hypothesis, and the possibility that PIC induces expression of additional chemokines and cytokines (previously reported as NF-\u03baB dependent) in pancreatic \u03b2-cells, was investigated in the present study. We observed that the PIC-responsive region in the Fas promoter is located between nucleotides \u2212223 and \u221254. Site-directed mutations at the NF-\u03baB and CCAAT\/enhancer binding protein-binding sites prevented PIC-induced Fas promoter activity. Increased Fas promoter activity was paralleled by enhanced susceptibility of PIC + cytokine-treated \u03b2-cells to apoptosis induced by Fas ligand. \u03b2-Cell infection with the NF-\u03baB inhibitor AdI\u03baB(SA)2 prevented both necrosis and apoptosis induced by PIC + IL-1\u03b2 or PIC + IFN-\u03b3. Messenger RNAs for several chemokines and one cytokine were induced by PIC, alone or in combination with IFN-\u03b3, in pancreatic \u03b2-cells. These included IP-10, interferon-\u03b3-inducible protein-10, IL-15, macrophage chemoattractant protein-1, fractalkine, and macrophage inflammatory protein-3\u03b1. There was not, however, induction of IL-1\u03b2 expression. We propose that dsRNA, generated during a viral infection, may contribute for \u03b2-cell demise by both inducing expression of chemokines and IL-15, putative contributors for the build-up of insulitis, and by synergizing with locally produced cytokines to induce \u03b2-cell apoptosis. Activation of the transcription factor NF-\u03baB plays a central role in at least part of the deleterious effects of dsRNA in pancreatic \u03b2-cells.<\/jats:p>","DOI":"10.1210\/endo.143.4.8737","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T16:12:17Z","timestamp":1389197537000},"page":"1225-1234","source":"Crossref","is-referenced-by-count":46,"title":["Double-Stranded RNA Cooperates with Interferon-\u03b3 and IL-1\u03b2 to Induce Both Chemokine Expression and Nuclear Factor-\u03baB-Dependent Apoptosis in Pancreatic \u03b2-Cells: Potential Mechanisms for Viral-Induced Insulitis and \u03b2-Cell Death in Type 1 Diabetes Mellitus"],"prefix":"10.1210","volume":"143","author":[{"given":"Dongbo","family":"Liu","sequence":"first","affiliation":[{"name":"Gene Expression Unit, Diabetes Research Center, Vrije Universiteit Brussel and Labaoratory of Experimental Medicine, Free University, Brussels, Brussels B-1070, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra K.","family":"Cardozo","sequence":"additional","affiliation":[{"name":"Gene Expression Unit, Diabetes Research Center, Vrije Universiteit Brussel and Labaoratory of Experimental Medicine, Free University, Brussels, Brussels B-1070, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine I.","family":"Darville","sequence":"additional","affiliation":[{"name":"Gene Expression Unit, Diabetes Research Center, Vrije Universiteit Brussel and Labaoratory of Experimental Medicine, Free University, Brussels, Brussels B-1070, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"De\u0301cio L.","family":"Eizirik","sequence":"additional","affiliation":[{"name":"Gene Expression Unit, Diabetes Research Center, Vrije Universiteit Brussel and Labaoratory of Experimental Medicine, Free University, Brussels, Brussels B-1070, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071619324186900_R1","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1056\/NEJM199411243312107","article-title":"The pathogenesis of insulin-dependent diabetes mellitus.","volume":"331","author":"Atkinson","year":"1994","journal-title":"N Engl J Med"},{"key":"2020071619324186900_R2","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/0896-8411(95)90001-2","article-title":"Insulin-dependent diabetes mellitus as a \u03b2-cell targeted disease of immunoregulation.","volume":"8","author":"Bach","year":"1995","journal-title":"J Autoimmun"},{"key":"2020071619324186900_R3","doi-asserted-by":"crossref","first-page":"413","DOI":"10.3109\/07853899708999371","article-title":"Viruses and other perinatal exposures as initiating events for \u03b2-cell destruction.","volume":"29","author":"Dahlquist","year":"1997","journal-title":"Ann Med"},{"key":"2020071619324186900_R4","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s001250051614","article-title":"The role of viruses in type I diabetes: two distinct cellular and molecular pathogenic mechanisms of virus-induced diabetes in animals.","volume":"44","author":"Jun","year":"2001","journal-title":"Diabetologia"},{"key":"2020071619324186900_R5","first-page":"432","article-title":"Mechanisms of coxsackievirus-induced damage to human pancreatic \u03b2-cells.","volume":"85","author":"Roivainen","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071619324186900_R6","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/clinids\/7.2.207","article-title":"Is insulin-dependent diabetes mellitus caused by coxsackievirus B infection? 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