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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.
 Previous Article | Next Article 
Submitted June 17, 2005
Accepted September 28, 2005
Interferon regulatory factor 3 is involved in Toll like receptor(TLR)4- and TLR3-induced IL-12p35 gene activation
Stanislas Goriely, Celine Molle, Muriel Nguyen, Valentina Albarani, Najate Ouled Haddou, Rongtuan Lin, Dominique De Wit, Veronique Flamand, Fabienne Willems, and Michel Goldman*
Institute for Medical Immunology, Universite Libre de Bruxelles, Charleroi, Belgium
Lady Davis Institute for Medical Research, McGill University, Montreal, Canada
* Corresponding author; email: mgoldman{at}ulb.ac.be.
Interleukin (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 IRF-3 in IL-12p35 gene transactivation. First, a binding site for IRF-3 named 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 cells stimulated by lipopolysaccharide (LPS) or PolyI:C. Ectopic expression of IRF-3 was found to upregulate 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 LPS-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.
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