title: TLR9 transcriptional regulation in response to double-stranded DNA viruses.
abstract: The stimulation of TLRs by pathogen-derived molecules leads to the production of proinflammatory cytokines. Because uncontrolled inflammation can be life threatening, TLR regulation is important; however, few studies have identified the signaling pathways that contribute to the modulation of TLR expression. In this study, we examined the relationship between activation and the transcriptional regulation of TLR9. We demonstrate that infection of primary human epithelial cells, B cells, and plasmacytoid dendritic cells with dsDNA viruses induces a regulatory temporary negative-feedback loop that blocks TLR9 transcription and function. TLR9 transcriptional downregulation was dependent on TLR9 signaling and was not induced by TLR5 or other NF-κB activators, such as TNF-α. Engagement of the TLR9 receptor induced the recruitment of a suppressive complex, consisting of NF-κBp65 and HDAC3, to an NF-κB cis element on the TLR9 promoter. Knockdown of HDAC3 blocked the transient suppression in which TLR9 function was restored. These results provide a framework for understanding the complex pathways involved in transcriptional regulation of TLR9, immune induction, and inflammation against viruses.
authors.affiliation: International Center for Infectiology Research, University of Lyon, Lyon 69007, France; Inserm, U1111, Lyon 69007, France; Ecole Normale Supérieure de Lyon, Lyon 69007, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69100, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon 69007, France; Oncovirus et l'immunité innée, Hospices Civils de Lyon Sud, Pierre Benite, 69495 France;
authors.forename: Claudia
authors.initials: C
authors.lastname: Zannetti
authors.affiliation: International Center for Infectiology Research, University of Lyon, Lyon 69007, France; Inserm, U1111, Lyon 69007, France; Ecole Normale Supérieure de Lyon, Lyon 69007, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69100, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon 69007, France; Oncovirus et l'immunité innée, Hospices Civils de Lyon Sud, Pierre Benite, 69495 France;
authors.forename: Peggy
authors.initials: P
authors.lastname: Parroche
authors.affiliation: International Center for Infectiology Research, University of Lyon, Lyon 69007, France; Inserm, U1111, Lyon 69007, France; Ecole Normale Supérieure de Lyon, Lyon 69007, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69100, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon 69007, France; Oncovirus et l'immunité innée, Hospices Civils de Lyon Sud, Pierre Benite, 69495 France;
authors.forename: Marine
authors.initials: M
authors.lastname: Panaye
authors.affiliation: International Center for Infectiology Research, University of Lyon, Lyon 69007, France; Inserm, U1111, Lyon 69007, France; Ecole Normale Supérieure de Lyon, Lyon 69007, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69100, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon 69007, France; Oncovirus et l'immunité innée, Hospices Civils de Lyon Sud, Pierre Benite, 69495 France;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Roblot
authors.affiliation: International Center for Infectiology Research, University of Lyon, Lyon 69007, France; Inserm, U1111, Lyon 69007, France; Ecole Normale Supérieure de Lyon, Lyon 69007, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69100, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon 69007, France;
authors.forename: Henri
authors.initials: H
authors.lastname: Gruffat
authors.affiliation: International Center for Infectiology Research, University of Lyon, Lyon 69007, France; Inserm, U1111, Lyon 69007, France; Ecole Normale Supérieure de Lyon, Lyon 69007, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69100, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon 69007, France;
authors.forename: Evelyne
authors.initials: E
authors.lastname: Manet
authors.affiliation: International Center for Infectiology Research, University of Lyon, Lyon 69007, France; Inserm, U1111, Lyon 69007, France; Ecole Normale Supérieure de Lyon, Lyon 69007, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69100, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon 69007, France;
authors.forename: Anne Laure
authors.initials: AL
authors.lastname: Debaud
authors.affiliation: Etablissement Français du Sang-Université Joseph Fourier-Inserm U823, Immunobiologie et Immunothérapie des cancers, Grenoble 38000, France; and.
authors.forename: Joel
authors.initials: J
authors.lastname: Plumas
authors.affiliation: Centre de recherche en cancérologie, Unité Mixte de Recherche, Inserm 1052, Centre National de la Recherche Scientifique 5286, Centre Léon Bérard, Lyon 69008, France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Vey
authors.affiliation: Centre de recherche en cancérologie, Unité Mixte de Recherche, Inserm 1052, Centre National de la Recherche Scientifique 5286, Centre Léon Bérard, Lyon 69008, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Caux
authors.affiliation: Centre de recherche en cancérologie, Unité Mixte de Recherche, Inserm 1052, Centre National de la Recherche Scientifique 5286, Centre Léon Bérard, Lyon 69008, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bendriss-Vermare
authors.affiliation: International Center for Infectiology Research, University of Lyon, Lyon 69007, France; Inserm, U1111, Lyon 69007, France; Ecole Normale Supérieure de Lyon, Lyon 69007, France; Université Claude Bernard Lyon 1, Centre International de Recherche en Infectiologie, Lyon 69100, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5308, Lyon 69007, France; Oncovirus et l'immunité innée, Hospices Civils de Lyon Sud, Pierre Benite, 69495 France; uzma.hasan@inserm.fr.
authors.forename: Uzma Ayesha
authors.initials: UA
authors.lastname: Hasan
mesh_terms: D000818:Animals; D004266:DNA Virus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004267:DNA Viruses / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology*; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D051217:Toll-Like Receptor 9; D051996:Transcription Factor RelA; D000099186:Histone Deacetylase 3; C498143:RELA protein, human; C498144:Rela protein, mouse; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse