Toll-like Receptor 3 and STAT-1 Contribute to Double-stranded RNA+ Interferon-γ-induced Apoptosis in Primary Pancreatic β-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-γ (IFN-γ), triggers β-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 β-cells to dsRNA in combination with IFN-α, -β, or -γ significantly increases apoptosis. Moreover, dsRNA induces TLR3 mRNA expression and activates NF-κB and the IFN-β promoter in a TRIF-dependent manner. dsRNA also induces an early (1 h) and sustained increase in IFN-β mRNA expression, and blocking IFN-β with a specific antibody partially prevents PIC plus IFN-γ-induced β-cell death. On the other hand, dsRNA plus IFN-γ 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 β-cells against dsRNA plus IFN-γ-induced β-cell apoptosis. This study suggests that dsRNA plus IFN-γ triggers β-cell apoptosis by two complementary pathways, namely TLR3-TRIF-NF-κB and STAT-1.