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


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.
Dogusan
Zeynep
Z
Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808, CP 618, B-1070 Brussels, Belgium.
García
Mónica
M
Flamez
Daisy
D
Alexopoulou
Lena
L
Goldman
Michel
M
Gysemans
Conny
C
Mathieu
Chantal
C
Libert
Claude
C
Eizirik
Decio L
DL
Rasschaert
Joanne
J
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D016899:Interferon-beta / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D050838:Interferon Regulatory Factor-3; D012330:RNA, Double-Stranded; C519703:TLR3 protein, mouse; C530472:TLR3 protein, rat; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D011070:Poly I-C