title: IRF-5 and NF-κB p50 co-regulate IFN-β and IL-6 expression in TLR9-stimulated human plasmacytoid dendritic cells.
abstract: Synthetic oligonucleotides (ODN) expressing CpG motifs mimic the ability of bacterial DNA to trigger the innate immune system via TLR9. Plasmacytoid dendritic cells (pDCs) make a critical contribution to the ensuing immune response. This work examines the induction of antiviral (IFN-β) and pro-inflammatory (IL-6) cytokines by CpG-stimulated human pDCs and the human CAL-1 pDC cell line. Results show that interferon regulatory factor-5 (IRF-5) and NF-κB p50 are key co-regulators of IFN-β and IL-6 expression following TLR9-mediated activation of human pDCs. The nuclear accumulation of IRF-1 was also observed, but this was a late event that was dependant on type 1 IFN and unrelated to the initiation of gene expression. IRF-8 was identified as a novel negative regulator of gene activation in CpG-stimulated pDCs. As variants of IRF-5 and IRF-8 were recently found to correlate with susceptibility to certain autoimmune diseases, these findings are relevant to our understanding of the pharmacologic effects of "K" ODN and the role of TLR9 ligation under physiologic, pathologic, and therapeutic conditions.
authors.affiliation: Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Folkert
authors.initials: F
authors.lastname: Steinhagen
authors.forename: Adelle P
authors.initials: AP
authors.lastname: McFarland
authors.forename: Luis G
authors.initials: LG
authors.lastname: Rodriguez
authors.forename: Poonam
authors.initials: P
authors.lastname: Tewary
authors.forename: Abigail
authors.initials: A
authors.lastname: Jarret
authors.forename: Ram
authors.initials: R
authors.lastname: Savan
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
mesh_terms: D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D050835:Interferon Regulatory Factors / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology; D052002:NF-kappa B p50 Subunit / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D015850:Interleukin-6; D052002:NF-kappa B p50 Subunit; D051217:Toll-Like Receptor 9; D016899:Interferon-beta
keywords: CpG oligonucleotide; Dendritic cell; IRF-5; NF-κB; TLR9