Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antiviral Agents / pharmacology*
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Blotting, Northern
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Humans
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Influenza A virus / pathogenicity
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Influenza, Human / immunology
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Influenza, Human / metabolism
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Influenza, Human / pathology
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Interferon Regulatory Factor-1 / metabolism
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Interferon-alpha / pharmacology*
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Interleukins / genetics
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Interleukins / metabolism*
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Ligands
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects*
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Macrophages / metabolism
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Macrophages / virology
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Mice
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Poly I-C / pharmacology
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Promoter Regions, Genetic / genetics
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Protein Subunits
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Respirovirus Infections / immunology
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Respirovirus Infections / metabolism
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Respirovirus Infections / pathology
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Response Elements
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Sendai virus / pathogenicity
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / metabolism
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Toll-Like Receptor 3 / genetics
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Toll-Like Receptor 3 / metabolism
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / metabolism
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Toll-Like Receptor 8 / genetics
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Toll-Like Receptor 8 / metabolism
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Toll-Like Receptors / agonists
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Toll-Like Receptors / genetics
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Toll-Like Receptors / metabolism*
Substances
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Antiviral Agents
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Interferon Regulatory Factor-1
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Interferon-alpha
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Interleukins
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Ligands
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Lipopolysaccharides
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MYDGF protein, human
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Protein Subunits
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Toll-Like Receptor 2
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptor 8
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Toll-Like Receptors
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Poly I-C