Toll-like receptor 3 and STAT-1 contribute to double-stranded RNA+ interferon-gamma-induced apoptosis in primary pancreatic beta-cells.
Viral infections and local production of cytokines probably contribute to the pathogenesis of Type 1 diabetes. The viral replicative intermediate double-stranded RNA (dsRNA, tested in the form of polyinosinic-polycytidylic acid, PIC), in combination with the cytokine interferon-gamma (IFN-gamma), triggers beta-cell apoptosis. We have previously observed by microarray analysis that PIC induces expression of several mRNAs encoding for genes downstream of Toll-like receptor 3 (TLR3) signaling pathway. In this report, we show that exposure of beta-cells to dsRNA in combination with IFN-alpha, -beta, or -gamma significantly increases apoptosis. Moreover, dsRNA induces TLR3 mRNA expression and activates NF-kappaB and the IFN-beta promoter in a TRIF-dependent manner. dsRNA also induces an early (1 h) and sustained increase in IFN-beta mRNA expression, and blocking IFN-beta with a specific antibody partially prevents PIC plus IFN-gamma-induced beta-cell death. On the other hand, dsRNA plus IFN-gamma does not induce apoptosis in INS-1E cells, and expression of TLR3 and type I IFNs mRNAs is not detected in these cells. Of note, disruption of the STAT-1 signaling pathway protects beta-cells against dsRNA plus IFN-gamma-induced beta-cell apoptosis. This study suggests that dsRNA plus IFN-gamma triggers beta-cell apoptosis by two complementary pathways, namely TLR3-TRIF-NF-kappaB and STAT-1.
Rasschaert
Joanne
J
Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808, CP 618, B-1070 Brussels, Belgium. jrasscha@ulb.ac.be
Ladrière
Laurence
L
Urbain
Maryse
M
Dogusan
Zeynep
Z
Katabua
Bitty
B
Sato
Shintaro
S
Akira
Shizuo
S
Gysemans
Conny
C
Mathieu
Chantal
C
Eizirik
Decio L
DL
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology / Q000821:virology*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D012330:RNA, Double-Stranded; D051381:Rats; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000502:physiology*
D000998:Antiviral Agents; D012330:RNA, Double-Stranded; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D007371:Interferon-gamma