Double-stranded RNA induces pancreatic beta-cell apoptosis by activation of the toll-like receptor 3 and interferon regulatory factor 3 pathways.

2008

Dogusan, Zeynep
García, Mónica
Flamez, Daisy
Alexopoulou, Lena
Goldman, Michel
Gysemans, Conny
Mathieu, Chantal
Libert, Claude
Eizirik, Decio L.
Rasschaert, Joanne

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 (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-kappaB (NF-kappaB) and IRF-3 activation and beta-cell apoptosis. PICin activated NF-kappaB and IRF-3 in a TLR3-independent manner, induced eukaryotic initiation factor 2 alpha phosphorylation, and triggered a massive production of interferon (IFN)-beta. This contributed to beta-cell death, as islet cells from IFNAR1(-/-) or IRF-3(-/-) mice were protected against PICin-induced apoptosis. CONCLUSIONS: PICex and PICin trigger beta-cell apoptosis via the TLR3 pathway or IRF-3 signaling, respectively. Execution of PICin-mediated apoptosis depends on autocrine effects of type I IFNs.
Journal Article
Research Support, Non-U.S. Gov't
info:eu-repo/semantics/published

Sciences bio-médicales et agricoles; Animals; Cell Survival; Cells, Cultured; Insulin-Secreting Cells -- cytology; Insulin-Secreting Cells -- physiology; Interferon Regulatory Factor-3 -- physiology; Interferon-beta -- biosynthesis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Poly I-C -- pharmacology; RNA, Double-Stranded -- genetics; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Toll-Like Receptor 3 -- deficiency; Toll-Like Receptor 3 -- genetics; Toll-Like Receptor 3 -- physiology; info:eu-repo/semantics/article; info:ulb-repo/semantics/articlePeerReview; info:ulb-repo/semantics/openurl/article

Open access content. Open access content
1 full-text file(s): info:eu-repo/semantics/restrictedAccess

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English

EQY oai:dipot.ulb.ac.be:2013/51081
uri/info:doi/10.2337/db07-0844
uri/info:pii/db07-0844
uri/info:pmid/18223009
uri/info:scp/48449098774
1363713358

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