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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.
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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.
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