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Multiple NF-B and IFN Regulatory Factor Family Transcription Factors Regulate CCL19 Gene Expression in Human Monocyte-Derived Dendritic Cells¹

Taija E. Pietilä^2,*, Ville Veckman^*, Anne Lehtonen, Rongtuan Lin, John Hiscott and Ilkka Julkunen^*

^* Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland; Molecular Cancer Biology Program, Institute of Biomedicine, Biomedicum Helsinki, Finland; and Lady Davis Institute for Medical Research, Department of Microbiology and Immunology, Department of Medicine, and Department of Oncology, McGill University, Montreal, Canada

CCL19 chemokine has a central role in dendritic cell (DC) biology regulating DC traffic and recruitment of naive T cells to the vicinity of activated DCs. In this study, we have analyzed the regulation of CCL19 gene expression in human monocyte-derived DCs. DCs infected with Salmonella enterica or Sendai virus produced CCL19 at late times of infection. The CCL19 promoter was identified as having two putative NF-B binding sites and one IFN-stimulated response element (ISRE). Transcription factor binding experiments demonstrated that Salmonella or Sendai virus infection increased the binding of classical p50+p65 and alternative p52+RelB NF-B proteins to both of the CCL19 promoter NF-B elements. Interestingly, Salmonella or Sendai virus infection also increased the binding of multiple IFN regulatory factors (IRFs), STAT1, and STAT2, to the ISRE element. Enhanced binding of IRF1, IRF3, IRF7, and IRF9 to the CCL19 promoter ISRE site was detected in Salmonella or Sendai virus-infected cell extracts. The CCL19 promoter in a luciferase reporter construct was activated by the expression of NF-B p50+p65 or p52+RelB dimers. IRF1, IRF3, and IRF7 proteins also activated CCL19 promoter in the presence of Sendai virus infection. CCL19 promoter constructs mutated at NF-B and/or ISRE sites were only weakly activated. Ectopic expression of RIG-I (RIG-I, CARDIF) or TLR3/4 (TRIF, MyD88, IKK, or TBK1) signaling pathway components induced CCL19 promoter activity, suggesting that these pathways are important in CCL19 gene expression. Our experiments reveal that expression of the CCL19 gene is regulated by a combined action of several members of the NF-B, IRF, and STAT family transcription factors.

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 This work was supported by the Medical Research Council of the Academy of Finland and the Sigrid Juselius Foundation.

² Address correspondence and reprint requests to Dr. Taija E. Pietilä, Department of Viral Diseases and Immunology, National Public Health Institute, Mannerheimintie 166, FI-00300 Helsinki, Finland. E-mail address: taija.pietila{at}ktl.fi

³ Abbreviations used in this paper: DC, dendritic cell; IRF, IFN regulatory factor; ISRE, IFN-stimulated response element; ISGF3, IFN-stimulated gene factor 3; MOI, multiplicity of infection; PDTC, pyrrolidine dithiocarbamate; DEM, diethyl maleate; CsA, cyclosporin A; IKK, inducible IB kinase; TBK1, Tank binding kinase 1; TRIF, Toll/IL-1R homology domain containing adaptor protein-inducing IFN-.

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