Toll-Like Receptor 3 Mediates a More Potent Antiviral Response Than Toll-Like Receptor 4

Abstract

We have recently described an IFN regulatory factor 3-mediated antiviral gene program that is induced by both Toll-like receptor (TLR)3 and TLR4 ligands. In our current study, we show that activation of IFN/viral response gene expression in primary macrophage cells is stronger and prolonged with TLR3 stimulation compared with that of TLR4. Our data also reveal that the cytoplasmic tails of both TLR3 and TLR4 can directly interact with myeloid differentiation factor 88 (MyD88). However, although Toll/IL-1 receptor homology domain-containing adaptor protein/MyD88 adaptor-like is able to associate with TLR4, we were unable to detect any interaction between Toll/IL-1 receptor homology domain-containing adaptor protein/MyD88 adaptor-like and TLR3. By using quantitative real-time PCR assays, we found that TLR3 expression is inducible by both TLR3 and TLR4 ligands, while TLR4 expression is not inducible by these same stimuli. Furthermore, using cells derived from mice deficient in the IFN-αβR, we show that both TLR3 and TLR4 require IFN-β autocrine/paracrine feedback to induce TLR3 expression and activate/enhance genes required for antiviral activity. More specifically, a subset of antiviral genes is initially induced independent of IFN-β, yet the cytokine further enhances expression at later time points. This was in contrast to a second set of genes (including TLR3) that is induced only after IFN-β production. Taken together, our data argue that, despite both TLR3 and TLR4 being able to use IFN-β to activate/enhance antiviral gene expression, TLR3 uses multiple mechanisms to enhance and sustain the antiviral response more strongly than TLR4.

Toll-like receptor 3 ligand-induced antiviral response in mouse osteoblastic cells

“…It is known that IFN-ß induces both TLR3 and CXCL10 mRNA leading to STAT1 phosphorylation on bone marrow macrophages (23). In the present study, we revealed that poly(I):poly(C) induced STAT1 activation on osteoblastic E1 cells and this effect was blocked by the addition of an anti-IFN-ß neutralizing antibody.…”

“…Our study revealed that poly(I):poly(C) up-regulated TLR3 expression in E1 cells. Doyle et al (23) reported that treatment of murine bonederived macrophages with a TLR3 ligand induced TLR3 mRNA expression. They also reported that stimulating macrophages with IFN-ß resulted in a dose-dependent upregulation of TLR3 mRNA.…”

“…1C). (23) revealed that stimulating primary macrophage cells with IFN-ß resulted in a dose-dependent up-regulation of TLR3 mRNA. Thus, we investigated whether exogenous IFN-ß could increase the level of TLR3 mRNA in osteoblastic cells.…”

Identification and functional characterizations of a novel TRIF gene from grass carp (Ctenopharyngodon idella)

“…TRIF, also known as TICAM-1 (TIR domain-containing adapter molecule 1), plays an essential role in TLR3-and TLR4-mediated interferon-b (IFN-b) activation through interferon regulatory factor 3/7 (IRF3/7)-dependent mechanism (Doyle et al, 2003;Fitzgerald et al, 2003). In piscine cells, both fugu Takifugu rubripes TLR3 (fgTLR3) and fgTLR22 employ the TRIF adaptor to induce IFN responses upon virus infection (Oshiumi et al, 2003;Matsuo et al, 2008).…”

Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses

“…[8][9][10][11][12] In the lifecycle of RNA viruses, double-stranded RNA (dsRNA) is generated and recognized by TLR3. 13,14 The activation of TLR3 results in the activation of interferon regulatory factor (IRF)-3, which is a key regulator of the induction of type I interferons (IFN), including IFN-␤, which are crucial mediators of the antiviral response. 15,16 Persistent HCV infection probably results from the disruption of host immune responses by HCV proteins.…”