IFN-alpha regulates Toll-like receptor-mediated IL-27 gene expression in human macrophages.
IL-27 is a novel member of the IL-12 cytokine family. IL-27 has pro- and anti-inflammatory properties, and it controls the responses of adaptive immunity. It promotes the differentiation of naïve Th cells and suppresses the effector functions of Th17 cells. Biologically active IL-27 is a heterodimer composed of EBV-induced gene 3 (EBI3) and p28 proteins. We report that TLR-dependent expression of IL-27 in human macrophages is mediated by IFN-alpha. Stimulation of macrophages with agonists for TLR3 {polyinosinic:polycytidylic acid [poly(I:C)]}, TLR4 (LPS), or TLR7/8 (R848) results in concurrent expression of EBI3 and p28. The p28 expression is inhibited with neutralizing anti-IFN-alpha antibodies. Unlike poly(I:C), LPS, and R848, TLR2 agonist (S)-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser(S)-Lys4-OH trihydrochloride does not stimulate macrophages to produce IFN-alpha, and therefore, it is not able to turn on the expression of p28. There is an IFN-stimulated response element (ISRE) in the p28 gene promoter. IFN-alpha enhances the expression of IFN regulatory factor 1 (IRF-1) in macrophages and induces binding of IRF-1 to the p28 ISRE site. The data provide a mechanistic basis for the IFN-alpha-mediated activation of IL-27. The data emphasize a role of IFN-alpha in immune responses, which rely on the recognition of pathogens by TLRs.
Pirhonen
Jaana
J
Department of Viral Diseases and Immunology, National Public Health Institute, Mannerheimintie 166, FI-00300, Helsinki, Finland. jaana.pirhonen@ktl.fi
Sirén
Jukka
J
Julkunen
Ilkka
I
Matikainen
Sampsa
S
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D006801:Humans; D009980:Influenza A virus / Q000472:pathogenicity; D007251:Influenza, Human / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D021122:Protein Subunits; D010253:Respirovirus Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020218:Response Elements; D029082:Sendai virus / Q000472:pathogenicity; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D000998:Antiviral Agents; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; D007378:Interleukins; D008024:Ligands; D008070:Lipopolysaccharides; C464565:MYDGF protein, human; D021122:Protein Subunits; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors; D011070:Poly I-C