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Double-Stranded RNA Cooperates with Interferon- and IL-1ß to Induce Both Chemokine Expression and Nuclear Factor-B-Dependent Apoptosis in Pancreatic ß-Cells: Potential Mechanisms for Viral-Induced Insulitis and ß-Cell Death in Type 1 Diabetes Mellitus

Gene Expression Unit, Diabetes Research Center, Vrije Universiteit Brussel and Labaoratory of Experimental Medicine, Free University, Brussels, Brussels B-1070, Belgium

Address all correspondence and requests for reprints to: Décio L. Eizirik, Laboratory of Experimental Medicine, Free University Brussels, 808 Route de Lennik, CP 618, B-1070 Brussels, Belgium. E-mail: . deizirik{at}ulb.ac.be

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- (IFN-) and/or IL-1ß, results in nitric oxide production, Fas expression, ß-cell dysfunction, and death. Activation of the transcription nuclear factor-B (NF-B) is required for PIC-induced inducible nitric oxide synthase expression in ß-cells, and we hypothesized that this transcription factor may also participate in PIC-induced Fas expression and ß-cell apoptosis. This hypothesis, and the possibility that PIC induces expression of additional chemokines and cytokines (previously reported as NF-B dependent) in pancreatic ß-cells, was investigated in the present study. We observed that the PIC-responsive region in the Fas promoter is located between nucleotides -223 and -54. Site-directed mutations at the NF-B 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 ß-cells to apoptosis induced by Fas ligand. ß-Cell infection with the NF-B inhibitor AdIB^(SA)2 prevented both necrosis and apoptosis induced by PIC + IL-1ß or PIC + IFN-. Messenger RNAs for several chemokines and one cytokine were induced by PIC, alone or in combination with IFN-, in pancreatic ß-cells. These included IP-10, interferon--inducible protein-10, IL-15, macrophage chemoattractant protein-1, fractalkine, and macrophage inflammatory protein-3. There was not, however, induction of IL-1ß expression. We propose that dsRNA, generated during a viral infection, may contribute for ß-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 ß-cell apoptosis. Activation of the transcription factor NF-B plays a central role in at least part of the deleterious effects of dsRNA in pancreatic ß-cells.

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