title: Essential role for IKKβ in production of type 1 interferons by plasmacytoid dendritic cells.
abstract: Plasmacytoid dendritic cells (pDCs) are characterized by their ability to produce high levels of type 1 interferons in response to ligands that activate TLR7 and TLR9, but the signaling pathways required for IFN production are incompletely understood. Here we exploit the human pDC cell line Gen2.2 and improved pharmacological inhibitors of protein kinases to address this issue. We demonstrate that ligands that activate TLR7 and TLR9 require the TAK1-IKKβ signaling pathway to induce the production of IFNβ via a pathway that is independent of the degradation of IκBα. We also show that IKKβ activity, as well as the subsequent IFNβ-stimulated activation of the JAK-STAT1/2 signaling pathway, are essential for the production of IFNα by TLR9 ligands. We further show that TLR7 ligands CL097 and R848 fail to produce significant amounts of IFNα because the activation of IKKβ is not sustained for a sufficient length of time. The TLR7/9-stimulated production of type 1 IFNs is inhibited by much lower concentrations of IKKβ inhibitors than those needed to suppress the production of NFκB-dependent proinflammatory cytokines, such as IL-6, suggesting that drugs that inhibit IKKβ may have a potential for the treatment of forms of lupus that are driven by self-RNA and self-DNA-induced activation of TLR7 and TLR9, respectively.
authors.affiliation: MRC Protein Phosphorylation Unit, The Sir James Black Centre, College of Life Sciences, University of Dundee, Scotland DD1 5EH, United Kingdom.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pauls
authors.forename: Natalia
authors.initials: N
authors.lastname: Shpiro
authors.forename: Mark
authors.initials: M
authors.lastname: Peggie
authors.forename: Erick R
authors.initials: ER
authors.lastname: Young
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Sorcek
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053612:Janus Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C508600:IL6 protein, human; D016898:Interferon-alpha; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; C495348:TLR7 protein, human; C495371:TLR9 protein, human; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D016899:Interferon-beta; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D053612:Janus Kinases; D051550:I-kappa B Kinase