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Blood, 1 February 2006, Vol. 107, No. 3, pp. 1078-1084. Prepublished online as a Blood First Edition Paper on October 11, 2005; DOI 10.1182/blood-2005-06-2416. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-06-2416v1 107/3/1078    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Goriely, S. Articles by Goldman, M. Search for Related Content PubMed PubMed Citation Articles by Goriely, S. Articles by Goldman, M. Related Collections Immunobiology Signal Transduction Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Interferon regulatory factor 3 is involved in Toll-like receptor 4 (TLR4)- and TLR3-induced IL-12p35 gene activation Stanislas Goriely, Céline Molle, Muriel Nguyen, Valentina Albarani, Najate Ouled Haddou, Rongtuan Lin, Dominique De Wit, Véronique Flamand, Fabienne Willems, and Michel Goldman From the Institute for Medical Immunology (IMI), Université Libre de Bruxelles, Charleroi, Belgium; and Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada. Interleukin-12 (IL-12) is a heterodimeric cytokine produced by dendritic cells (DCs) in response to Toll-like receptor (TLR) ligation. While the mechanisms regulating IL-12p40 chain gene expression are well characterized, molecular events involved in IL-12p35 chain gene activation remain to be clarified. Since IL-12p35 mRNA was induced in human DCs activated through TLR3 or TLR4 but not TLR2, we investigated the potential role of interferon regulatory factor 3 (IRF-3) in IL-12p35 gene transactivation. First, a binding site for IRF-3 named interferon-stimulated response element-1 (ISRE-1) was identified in the human IL-12p35 promoter region between nucleotides -251 and -240. The ISRE-1 site was required for IL-12p35 gene activation in RAW 264.7 cells stimulated by lipopolysaccharide (LPS) or PolyI:C. Ectopic expression of IRF-3 was found to up-regulate IL-12p35 gene activation in the same system. Furthermore, chromatin immunoprecipitation (ChIP) studies demonstrated that IRF-3 is recruited to ISRE-1 site in TLR4- or TLR3-stimulated human DCs. Finally, experiments on DCs from IRF-3-deficient mice established that TLR4-induced IL-12p35 mRNA and IL-12p70 synthesis are impaired in absence of IRF-3. We conclude that IRF-3 binds to a critical cis-acting element in the IL-12p35 gene promoter and thereby represents a key factor for the induction of IL-12p70 synthesis in DCs. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Kempe, P. Heinz, E. Kokai, O. Devergne, N. Marx, and T. Wirth Epstein-Barr Virus-Induced Gene-3 Is Expressed in Human Atheroma Plaques Am. J. Pathol., July 1, 2009; 175(1): 440 - 447. [Abstract] [Full Text] [PDF] S. M. Makela, M. Strengell, T. E. Pietila, P. Osterlund, and I. Julkunen Multiple signaling pathways contribute to synergistic TLR ligand-dependent cytokine gene expression in human monocyte-derived macrophages and dendritic cells J. Leukoc. Biol., April 1, 2009; 85(4): 664 - 672. [Abstract] [Full Text] [PDF] E Sanchez, M. Gonzalez-Gay, J. Callejas-Rubio, N Ortego-Centeno, J. Sabio, J Jimenez-Alonso, L Mico, A Suarez, C Gutierrez, E de Ramon, et al. 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