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

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 5; pp. 1236 - 1245
• Main Authors: DOGUSAN, Zeynep, GARCIA, Monica, FLAMEZ, Daisy, ALEXOPONLOU, Lena, GOLDMAN, Michel, GYSEMANS, Conny, MATHIEN, Chantal, LIBERT, Claude, EIZIRIK, Decio L, RASSCHAERT, Joanne
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2008
• Subjects: Animals; Apoptosis; Biological and medical sciences; Cell Survival; Cells, Cultured; Diabetes. Impaired glucose tolerance; DNA binding proteins; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genetic aspects; Health aspects; Immunology; Influence; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - physiology; Interferon; Interferon Regulatory Factor-3 - physiology; Interferon-beta - biosynthesis; Life Sciences; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreatic beta cells; Poly I-C - pharmacology; Properties; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Double-Stranded - genetics; Toll-Like Receptor 3 - deficiency; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - physiology; Type 1 diabetes; Belgium; Endocrinopathy; RNA; Cell death; Diabetes mellitus; Cytokine; Langerhans islet; Interferon; β Cell; Endocrine pancreas; Apoptosis; Biological receptor
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db07-0844

Double-Stranded RNA Induces Pancreatic β-Cell Apoptosis by Activation of the Toll-Like Receptor 3 and Interferon Regulatory Factor 3 Pathways Zeynep Dogusan 1 , Mónica García 1 , Daisy Flamez 1 , Lena Alexopoulou 2 , Michel Goldman 3 , Conny Gysemans 4 , Chantal Mathieu 4 , Claude Libert 5 , Decio L. Eizirik 1 and Joanne Rasschaert 1 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 Abstract 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-κB (NF-κB) and IRF-3 activation and β-cell apoptosis. PICin activated NF-κB and IRF-3 in a TLR3-independent manner, induced eukaryotic initiation factor 2α 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. 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-κB, nuclear factor-κB PIC, polyinosinic-polycytidylic acid PKR, dsRNA-dependent protein kinase TLR, toll-like receptor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 25 January 2008. DOI: 10.2337/db07-0844. Additional information can be found in an online appendix at http://dx.doi.org/10.2337/db07-0844 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 18, 2008. Received July 22, 2007. DIABETES