IFN-alpha regulates TLR-dependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29.
Toll-like receptors (TLRs) mediate host cell activation by various microbial components. TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 are the receptors that have been associated with virus-induced immune response. We have previously reported that all these TLRs, except TLR9, are expressed at mRNA levels in human monocyte-derived macrophages. Here we have studied TLR2, TLR3, TLR4, and TLR7/8 ligand-induced IFN-alpha, IFN-beta, IL-28, and IL-29 expression in human macrophages. IFN-alpha pretreatment of macrophages was required for efficient TLR3 and TLR4 agonist-induced activation of IFN-alpha, IFN-beta, IL-28, and IL-29 genes. TLR7/8 agonist weakly activated IFN-alpha, IFN-beta, IL-28, and IL-29 genes, whereas TLR2 agonist was not able to activate these genes. IFN-alpha enhanced TLR responsiveness in macrophages by up-regulating the expression of TLR3, TLR4, and TLR7. IFN-alpha also enhanced the expression of TLR signaling molecules MyD88, TIR domain-containing adaptor inducing IFN-beta, IkappaB kinase-epsilon, receptor interacting protein 1, and IFN regulatory factor 7. Furthermore, the activation of transcription factor IFN regulatory factor 3 by TLR3 and TLR4 agonists was dependent on IFN-alpha pretreatment. In conclusion, our results suggest that IFN-alpha sensitizes cells to microbial recognition by up-regulating the expression of several TLRs as well as adapter molecules and kinases involved in TLR signaling.
Sirén
Jukka
J
Department of Microbiology, National Public Health Institute, Helsinki, Finland.
Pirhonen
Jaana
J
Julkunen
Ilkka
I
Matikainen
Sampsa
S
D000998:Antiviral Agents / Q000502:physiology; D002460:Cell Line; D002474:Cell-Free System / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics*; D007371:Interferon-gamma / Q000096:biosynthesis; D007372:Interferons; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics*; D008024:Ligands; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008562:Membrane Glycoproteins / Q000819:agonists / Q000096:biosynthesis / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists / Q000096:biosynthesis / Q000502:physiology*; D029082:Sendai virus / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D000095022:Interferon Lambda
D000998:Antiviral Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma; D007372:Interferons; D007378:Interleukins; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494257:IRF1 protein, human; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C495371:TLR9 protein, human