Double‐stranded RNA mediates interferon regulatory factor 3 activation and interleukin‐6 production by engaging Toll‐like receptor 3 in human brain astrocytes

Abstract

Toll‐like receptor 3 (TLR3) participates in the innate immune response by recognizing viral pathogens. In this study, human brain astrocytes were found to constitutively express TLR3, and this expression was increased by interferon‐γ (IFN‐γ) or double‐stranded RNA (dsRNA). Treatment employing dsRNA in astrocytes induced IFN regulatory factor 3 (IRF3) phosphorylation, dimer formation and nuclear translocation followed by STAT1 activation. This treatment also activated nuclear factor‐κB, p38 and c‐Jun N‐terminal kinase significantly, while activating extracellular signal‐regulated kinase to a lesser extent. Treatment with anti‐TLR3 antibody inhibited dsRNA‐mediated interleukin‐6 (IL‐6) production. In the presence of mitogen‐activated protein kinase inhibitors, astrocytes failed to secrete IL‐6 in response to dsRNA treatment. Therefore, dsRNA‐induced IL‐6 production is dependent on mitogen‐activated protein kinases and type I IFN production is dependent on IRF3 in brain astrocytes. These results suggest that brain inflammation, which produces inflammatory cytokines and type I IFNs, may enhance TLR3 expression in astrocytes. Additionally, upregulated TLR3 might modulate inflammatory processes by producing proinflammatory cytokines.