Diabetes
Author:
Keywords:
endoplasmic-reticulum stress, type-1 diabetes-mellitus, nf-kappa-b, messenger-rna, induced genes, nitric-oxide, expression, virus, gamma, mechanisms, Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, ENDOPLASMIC-RETICULUM STRESS, TYPE-1 DIABETES-MELLITUS, NF-KAPPA-B, MESSENGER-RNA, INDUCED GENES, NITRIC-OXIDE, EXPRESSION, VIRUS, GAMMA, MECHANISMS, Animals, Cell Survival, Cells, Cultured, Insulin-Secreting Cells, Interferon Regulatory Factor-3, Interferon-beta, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Poly I-C, RNA, Double-Stranded, Rats, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptor 3, 11 Medical and Health Sciences, 32 Biomedical and clinical sciences
Abstract:
Objective: Viral infections contribute to the pathogenesis of type 1 diabetes. Viruses, or viral products such as double-stranded RNA (dsRNA), affect pancreatic beta cell survival and trigger autoimmunity by unknown mechanisms. We presently investigated the mediators and downstream effectors of dsRNA-induced beta cell death. Research Design and Methods: Primary rat beta cells and islet cells from wild type, Toll-like receptor 3 (TLR3), type I interferon receptor (IFNAR1) or interferon regulatory factor 3 (IRF-3) knockout mice were exposed to external dsRNA (polyinosinic polycytidylic acid; PICex) or were transfected with dsRNA (PICin). Results: TLR3 signaling mediated PICex-induced NF-kappaB and IRF-3 activation and beta cell apoptosis. PICin activated NF-kappaB and IRF-3 in a TLR3-independent manner, induced eIF2alpha phosphorylation and triggered a massive production of IFN-beta. This contributed to beta cell death as islet cells from IFNAR1(-/-) or IRF-3(-/-) mice were protected against PICin-induced apoptosis. Conclusions: External and internal dsRNA trigger beta cell apoptosis via respectively the TLR3 pathway or IRF-3 signaling. Execution of PICin-mediated apoptosis depends on autocrine effects of type I IFNs.