Double-stranded RNA induces pancreatic β-cell apoptosis by activation of the toll-like receptor 3 and interferon regulatory factor 3 pathways
Diabetes, 2008•Am Diabetes Assoc
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 …
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 …
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.
Am Diabetes Assoc