HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Molle, C. Articles by Goriely, S. Search for Related Content PubMed PubMed Citation Articles by Molle, C. Articles by Goriely, S.

IL-27 Synthesis Induced by TLR Ligation Critically Depends on IFN Regulatory Factor 3¹

Céline Molle^*, Muriel Nguyen^*, Véronique Flamand^*, Joelle Renneson^*, François Trottein, Dominique De Wit^*, Fabienne Willems^*, Michel Goldman^* and Stanislas Goriely^2,*

^* Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium; and Institut National de la Recherche Médicale, Unité 547, Institut Pasteur de Lille, Lille, France

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- 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--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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The Institute for Medical Immunology was sponsored by the government of the Walloon Region and GlaxoSmithKline Biologicals. This study was supported by the Fonds National de la Recherche Scientifique and an Interuniversity Attraction Pole of the Belgian Federal Science Policy. S.G. was a Postdoctoral Researcher of the Fonds National de la Recherche Scientifique. V.F. was a Research Associate of the Fonds National de la Recherche Scientifique and J.R. was supported by a grant from the Fonds National de la Recherche Scientifique-Telévie program.

² Address correspondence and reprint requests to Dr. Stanislas Goriely, Institute for Medical Immunology, 8 rue Adrienne Bolland, B-6041 Charleroi-Gosselies, Belgium. E-mail address: stgoriel{at}ulb.ac.be

³ Abbreviations used in this paper: EIB3, EBV-induced gene 3; TIR, Toll/IL-1R; IRF, IFN regulatory factor; TRIF, TIR domain-containing adaptor inducing IFN-; DC, dendritic cell; moDC, monocyte-derived DC; BMDC, bone marrow-derived DC; hCMV, human CMV; MOI, multiplicity of infection; ISRE, IFN-stimulated response element; ChIP, chromatin immunoprecipitation; polyI:C, polyinosine-polycytidylic acid; Pam₃CSK₄, 2.3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser- Lys₄-OH; MyD88, myeloid differentiation factor 88.