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

Dogusan Z. D., Garcia M., Flamez D., Alexopoulou L., Goldman M., Gysemans C., ...Daha Fazla

Diabetes, cilt.57, sa.5, ss.1236-1245, 2008 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 57 Sayı: 5
  • Basım Tarihi: 2008
  • Doi Numarası: 10.2337/db07-0844
  • Dergi Adı: Diabetes
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.1236-1245
  • İstanbul Yeni Yüzyıl Üniversitesi Adresli: Hayır

Özet

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. © 2008 by the American Diabetes Association.