title: Stimulation of IRF-7 gene expression by tumor necrosis factor alpha: requirement for NFkappa B transcription factor and gene accessibility.
abstract: Interferon regulatory factor 7 (IRF-7) plays an important role in innate immunity, where, together with IRF-3, it controls the expression of interferon A/B genes as well as chemokine RANTES (regulated on activation normal T cell expressed and secreted). Previously, we characterized human IRF-7 promoter and showed that an interferon-stimulated response element site in the first intron binds interferon-stimulated gene factor 3 (ISGF3) and confers the response to interferon. Here we report the stimulation of IRF-7 expression by 12-O-tetradecanoylphorbol-13-acetate (TPA) and tumor necrosis factor alpha (TNFalpha) in human peripheral blood monocytes. Using promoter analysis in combination with electrophoretic mobility shift assays, we have demonstrated that an NFkappaB site located next to the TATA box, binds p50 and p65 heterodimer and is required for the induction of the IRF-7 gene by TPA and TNFalpha. In addition, we report stimulation of IRF-7 gene expression by topoisomerase II (TOPII) inhibitors. We show by chromatin immunoprecipitation assay that treatment with the TOPII inhibitor etoposide induces association of acetylated histone 3 with the promoter of IRF-7 gene, indicating that TOPII-mediated changes in chromatin structure could be responsible for the induction. This suggests that the IRF-7 gene is localized in the condensed area of the chromosome where it is inaccessible to transcription factors that would promote its constitutive expression.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center and the Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Runqing
authors.initials: R
authors.lastname: Lu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Moore
authors.forename: Paula M
authors.initials: PM
authors.lastname: Pitha
mesh_terms: D015152:Blotting, Northern; D002135:Calcium-Binding Proteins; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D017930:Genes, Reporter; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D050839:Interferon Regulatory Factor-7; D008156:Luciferases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050863:Synaptotagmin I; D050857:Synaptotagmins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D018946:Chemokine CCL5; D002843:Chromatin; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006657:Histones; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009419:Nerve Tissue Proteins; D050863:Synaptotagmin I; D059005:Topoisomerase II Inhibitors; D014409:Tumor Necrosis Factor-alpha; D050857:Synaptotagmins; D005047:Etoposide; D008156:Luciferases; D013755:Tetradecanoylphorbol Acetate