Title: Double-stranded RNA induces pancreatic beta-cell apoptosis by activation of the toll-like receptor 3 and interferon regulatory factor 3 pathways
Authors: Dogusan, Zeynep
García, Mónica
Flamez, Daisy
Alexopoulou, Lena
Goldman, Michel
Gysemans, Conny
Mathieu, Chantal
Libert, Claude
Eizirik, Decio Laks
Rasschaert, Joanne # ×
Issue Date: May-2008
Publisher: American Diabetes Association
Series Title: Diabetes vol:57 issue:5 pages:1236-1245
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.
ISSN: 0012-1797
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
Medical Clerkships Centers
× corresponding author
# (joint) last author

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