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Aims/hypothesis: Viral infections and local production of IFN-[gamma] might contribute to beta-cell dysfunction/death in Type 1 Diabetes. Double stranded RNA (dsRNA) accumulates in the cytosol of viral-infected cells, and exposure of purified rat beta cells to dsRNA (tested in the form of polyinosinic-polycytidylic acid, PIC) in combination with IFN-[gamma] results in beta-cell dysfunction and apoptosis. To elucidate the molecular mechanisms involved in PIC IFN-[gamma]-effects, we determined the global profile of genes modified by these agents in primary rat beta cells.

Methods: FACS-purified rat beta cells were cultured for 6 or 24 h in control condition or with IFN-[gamma], PIC or a combination of both agents. The gene expression profile was analysed in duplicate by high-density oligonucleotide arrays representing 5000 full-length genes and 3000 EST's. Changes of greater than or equal to 2.5-fold were considered as relevant.

Results: Following a 6- or 24-h treatment with IFN-[gamma], PIC or IFN-[gamma] and PIC, we observed changes in the expression of 51 to 189 genes. IFN-[gamma] modified the expression of MHC-related genes, and also of genes involved in beta-cell metabolism, protein processing, cytokines and signal transduction. PIC affected preferentially the expression of genes related to cell adhesion, cytokines and dsRNA signal transduction, transcription factors and MHC. PIC and/or IFN-[gamma] up-regulated the expression of several chemokines and cytokines that could contribute to mononuclear cell homing and activation during viral infection, while IFN-[gamma] induced a positive feedback on its own signal transduction. PIC IFN-[gamma] inhibited insulin and GLUT-2 expression without modifying pdx-1 mRNA expression.

Conclusion/interpretation: This study provides the first comprehensive characterization of the molecular responses of primary beta cells to dsRNA IFN-[gamma], two agents that are probably present in the beta cell milieu during the course of virally-induced insulitis and Type 1 Diabetes. Based on these findings, we propose an integrated model for the molecular mechanisms involved in dsRNA IFN-[gamma] induced beta-cell dysfunction and death.

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