RRC ID 1855
Author Goriely S, Molle C, Nguyen M, Albarani V, Haddou NO, Lin R, De Wit D, Flamand V, Willems F, Goldman M.
Title Interferon regulatory factor 3 is involved in Toll-like receptor 4 (TLR4)- and TLR3-induced IL-12p35 gene activation.
Journal Blood
Abstract 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.
Volume 107(3)
Pages 1078-84
Published 2006-2-1
DOI 10.1182/blood-2005-06-2416
PII 2005-06-2416
PMID 16219795
MeSH Animals Antiviral Agents / pharmacology Cell Line Chromatin Immunoprecipitation Dendritic Cells / cytology Dendritic Cells / immunology Humans Interferon Regulatory Factor-3 / deficiency Interferon Regulatory Factor-3 / immunology* Interleukin-12 / genetics Interleukin-12 / immunology* Interleukin-12 Subunit p35 Interleukin-12 Subunit p40 Lipopolysaccharides / pharmacology Mice Poly I-C / pharmacology Protein Subunits / genetics Protein Subunits / immunology* Response Elements / genetics Response Elements / immunology Toll-Like Receptor 3 / immunology* Toll-Like Receptor 4 / immunology* Transcription, Genetic / drug effects Transcription, Genetic / genetics Transcription, Genetic / immunology Up-Regulation / drug effects Up-Regulation / genetics Up-Regulation / immunology*
IF 16.601
Times Cited 69
Mice IRF-3 Knockout mice