Toll-like receptor 3 and STAT-1 contribute to double-stranded RNA+ interferon-gamma-induced apoptosis in primary pancreatic beta-cells

J Biol Chem. 2005 Oct 7;280(40):33984-91. doi: 10.1074/jbc.M502213200. Epub 2005 Jul 15.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Cell Line
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diabetes Mellitus, Type 1 / virology*
  • Insulin-Secreting Cells / physiology*
  • Interferon-gamma / pharmacology
  • Male
  • RNA, Double-Stranded
  • Rats
  • Rats, Wistar
  • STAT1 Transcription Factor / physiology*
  • Signal Transduction
  • Toll-Like Receptor 3 / physiology*

Substances

  • Antiviral Agents
  • RNA, Double-Stranded
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Interferon-gamma