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Published online before print August 7, 2007

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(Journal of Leukocyte Biology. 2007;82:1185-1192.)
© 2007 by Society for Leukocyte Biology

IFN- regulates Toll-like receptor-mediated IL-27 gene expression in human macrophages

Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland

¹ Correspondence: Department of Viral Diseases and Immunology, National Public Health Institute, Mannerheimintie 166, FI-00300, Helsinki, Finland. E-mail: jaana.pirhonen{at}ktl.fi

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-. 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- 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-, 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- 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--mediated activation of IL-27. The data emphasize a role of IFN- in immune responses, which rely on the recognition of pathogens by TLRs.

Key Words: interferon regulatory factor • IFN-stimulated response element • transcriptional activation • viral infection