Recognition of dsRNA by Toll-like receplor 3

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Toll-like receptor 3(TLR3) recognizes dsRNA and transmits signals to activate NF-κB and the IFN-β promoter independent of the adaptor molecules MyD88 and Mal/TIRAP. We have identified an alternative adaptor, designated Toll-interleukin 1 receptor domain(TIR)-containing adaptor molecule (TICAM)-1, that can physically bind the TIR domain of TLR3 and activate the IFN-β promoter in response to poly(I:C), a syntetic analog of dsRNA. TICAM-1, when overexpressed, activated NF-κB and interferon regulatory factor(IRF)-3, a critically important transcription factor for IFN-β gene expression. RNA interference-mediated knockdown of TLR3 or TICAM-1, but not of MyD88 or Mal/TIRAP, significantly reduced IFN-β production induced by poly(I:C) in human fibloblasts and HeLa cells. Thus, dsRNA-TLR3-dependent production of IFN-β is mediated mainly by TICAM-1. Furthermore, we cloned an additional adaptor molecule, TICAM-2, that physically bridges TLR4 and TICAM-1 and functionally transmits LPS-TLR4 signaling to TICAM-1, which in turn activates IRF-3 leading to produce IFN-β. This TICAM-1-dependent pathway forms part of the MyD88-independent cellular immune response. Immunofluorescence staining and con focal microscopic analysis using anti-human TLR3 mAb (TLR3.7) revealed that TLR3 localized to specific unidentified intracellular vesicles in both monocyte-derived immature DCs and CD11c^+ blood DCs. TLR3-mediated signaling required endosomal maturation. These results suggest that the TLR3-TICAM-1 pathway plays an important role in sensing the extracellular dsRNA, which participates in an antiviral immune response.