IL-27 synthesis induced by TLR ligation critically depends on IFN regulatory factor 3.
IL-27 is a heterodimeric cytokine composed of EBV-induced gene 3 and p28. Produced by dendritic cells (DCs) in response to TLR ligands, IL-27 recently emerged as a key regulator of inflammatory responses. In this study, we first demonstrate that Toll/IL-1R-containing adaptor inducing IFN-beta and its associated IFN regulatory factor (IRF) 3 transcription factor are critically involved in IL-27p28 expression in mouse DCs stimulated by TLR ligands. We then show that IL-27 serum levels are dramatically reduced in IRF3(-/-) upon LPS injection, indicating a critical role for IRF3 in TLR4-mediated IL-27 production in vivo. We identified an IRF3-binding site within the IL-27p28 promoter region which is required for IL-27p28 gene activation in reporter gene assays. In human DCs, IL-27p28 mRNA was preferentially induced by Toll/IL-1R-containing adaptor inducing IFN-beta-coupled TLR ligands and following CMV infection. Furthermore, chromatin immunoprecipitation studies demonstrate that IRF3 is recruited to the endogenous p28 promoter in TLR4-stimulated human DCs. We conclude that IRF3 activation is a master switch for IL-27 synthesis.
Molle
Céline
C
Institute for Medical Immunology, Université Libre de Bruxelles, 8 rue Adrienne Bolland, B-6041 Charleroi-Gosselies, Belgium.
Nguyen
Muriel
M
Flamand
Véronique
V
Renneson
Joelle
J
Trottein
François
F
De Wit
Dominique
D
Willems
Fabienne
F
Goldman
Michel
M
Goriely
Stanislas
S
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D003713:Dendritic Cells / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D018121:Receptors, Cytokine / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists; D051193:Toll-Like Receptors / Q000378:metabolism; D015533:Transcriptional Activation
D033942:Adaptor Proteins, Vesicular Transport; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D007378:Interleukins; D008070:Lipopolysaccharides; D015778:Minor Histocompatibility Antigens; D053594:Myeloid Differentiation Factor 88; D018121:Receptors, Cytokine; D017472:Receptors, Interleukin-1; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C499601:Ebi3 protein, mouse; C486767:Il27 protein, mouse; C476286:Ticam1 protein, mouse