title: Regulation of RANTES chemokine gene expression requires cooperativity between NF-kappa B and IFN-regulatory factor transcription factors.
abstract: Virus infection of host cells activates a set of cellular genes, including cytokines, IFNs, and chemokines, involved in antiviral defense and immune activation. Previous studies demonstrated that virus-induced transcriptional activation of a member of the human CC-chemokine RANTES required activation of the latent transcription factors IFN-regulatory factor (IRF)-3 and NF-kappa B via posttranslational phosphorylation. In the present study, we further characterized the regulatory control of RANTES transcription during virus infection using in vivo genomic footprinting analyses. IRF-3, the related IRF-7, and NF-kappa B are identified as important in vivo binding factors required for the cooperative induction of RANTES transcription after virus infection. Using fibroblastic or myeloid cells, we demonstrate that the kinetics and strength of RANTES virus-induced transcription are highly dependent on the preexistence of IRFs and NF-kappa B. Use of dominant negative mutants of either I kappa B-alpha or IRF-3 demonstrate that disruption of either pathway dramatically abolishes the ability of the other to bind and activate RANTES expression. Furthermore, coexpression of IRF-3, IRF-7, and p65/p50 leads to synergistic activation of RANTES promoter transcription. These studies reveal a model of virus-mediated RANTES promoter activation that involves cooperative synergism between IRF-3/IRF-7 and NF-kappa B factors.
authors.affiliation: Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Departments of Microbiology, McGill University, Montreal, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Génin
authors.forename: M
authors.initials: M
authors.lastname: Algarté
authors.forename: P
authors.initials: P
authors.lastname: Roof
authors.forename: R
authors.initials: R
authors.lastname: Lin
authors.forename: J
authors.initials: J
authors.lastname: Hiscott
mesh_terms: D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004357:Drug Synergism; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I / Q000502:physiology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D018108:Respirovirus / Q000235:genetics / Q000276:immunology; D020218:Response Elements / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D020298:U937 Cells
chemical_list: D018946:Chemokine CCL5; D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D016328:NF-kappa B; D014157:Transcription Factors