IRF3 mediates a TLR3/TLR4-specific antiviral gene program.
We have identified a subset of genes that is specifically induced by stimulation of TLR3 or TLR4 but not by TLR2 or TLR9. Further gene expression analyses established that upregulation of several primary response genes was dependent on NF-kappaB, commonly activated by several TLRs, and interferon regulatory factor 3 (IRF3), which was found to confer TLR3/TLR4 specificity. Also identified was a group of secondary response genes which are part of an autocrine/paracrine loop activated by the primary response gene product, interferon beta (IFNbeta). Selective activation of the TLR3/TLR4-IRF3 pathway potently inhibited viral replication. These results suggest that TLR3 and TLR4 have evolutionarily diverged from other TLRs to activate IRF3, which mediates a specific gene program responsible for innate antiviral responses.
D016475:3T3 Cells; D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D016328:NF-kappa B / Q000502:physiology; D019899:Paracrine Communication / Q000235:genetics; D010457:Peptidoglycan / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D018144:Rhadinovirus / Q000502:physiology*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014777:Virus Diseases / Q000276:immunology*; D014779:Virus Replication
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D020672:I-kappa B Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010457:Peptidoglycan; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014157:Transcription Factors; D016899:Interferon-beta