Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4.
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-alphabetaR, we show that both TLR3 and TLR4 require IFN-beta 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-beta, 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-beta production. Taken together, our data argue that, despite both TLR3 and TLR4 being able to use IFN-beta to activate/enhance antiviral gene expression, TLR3 uses multiple mechanisms to enhance and sustain the antiviral response more strongly than TLR4.
Doyle
Sean E
SE
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
O'Connell
Ryan
R
Vaidya
Sagar A
SA
Chow
Edward K
EK
Yee
Kathleen
K
Cheng
Genhong
G
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic / Q000235:genetics / Q000502:physiology; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000378:metabolism; D000998:Antiviral Agents / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D018142:Gammaherpesvirinae / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D053633:Receptor, Interferon alpha-beta; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000378:metabolism; D017471:Receptors, Interferon / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015534:Trans-Activators / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D000943:Antigens, Differentiation; D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D008024:Ligands; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D017472:Receptors, Interleukin-1; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C434984:TIRAP protein, human; C499045:TIRAP protein, mouse; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015534:Trans-Activators; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta