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Double-Stranded RNA Induces Pancreatic β-Cell Apoptosis by Activation of the Toll-Like Receptor 3 and Interferon Regulatory Factor 3 Pathways

¹ Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium
² Centre d'Immunologie de Marseille-Luminy, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de la Mediterranée, Marseille, France
³ Institute of Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
⁴ Laboratory of Experimental Medicine and Endocrinology (Legendo), Universitaire Ziekenhuizen Gasthuisberg O&N, Katholieke Universiteit Leuven, Leuven, Belgium
⁵ Department for Molecular Biomedical Research, VIB Ghent University, Ghent, Belgium

Corresponding author: Dr. Joanne Rasschaert, Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808, CP 618, B-1070 Brussels, Belgium. E-mail: jrasscha{at}ulb.ac.be

Abbreviations: ATF-4, activating transcription factor-4; CHOP, CCAAT/enhancer-binding protein homologous protein; dsRNA, double-stranded RNA; eIF, eukaryotic initiation factor; ER, endoplasmic reticulum; FACS, fluorescence-activated cell sorter; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; IFNAR1, type I interferon receptor; IFN, interferon; IL, interleukin; IRF, interferon regulatory factor; LF, lipofectamine; NF-B, nuclear factor-B; PIC, polyinosinic-polycytidylic acid; PKR, dsRNA-dependent protein kinase; TLR, toll-like receptor

OBJECTIVE— Viral infections contribute to the pathogenesis of type 1 diabetes. Viruses, or viral products such as double-stranded RNA (dsRNA), affect pancreatic β-cell survival and trigger autoimmunity by unknown mechanisms. We presently investigated the mediators and downstream effectors of dsRNA-induced β-cell death.

RESEARCH DESIGN AND METHODS— Primary rat β-cells and islet cells from wild-type, toll-like receptor (TLR) 3, type I interferon receptor (IFNAR1), or interferon regulatory factor (IRF)-3 knockout mice were exposed to external dsRNA (external polyinosinic-polycytidylic acid [PICex]) or were transfected with dsRNA ([PICin]).

RESULTS— TLR3 signaling mediated PICex-induced nuclear factor-B (NF-B) and IRF-3 activation and β-cell apoptosis. PICin activated NF-B and IRF-3 in a TLR3-independent manner, induced eukaryotic initiation factor 2 phosphorylation, and triggered a massive production of interferon (IFN)-β. This contributed to β-cell death, as islet cells from IFNAR1^–/– or IRF-3^–/– mice were protected against PICin-induced apoptosis.

CONCLUSIONS— PICex and PICin trigger β-cell apoptosis via the TLR3 pathway or IRF-3 signaling, respectively. Execution of PICin-mediated apoptosis depends on autocrine effects of type I IFNs.

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