title: CCAAT/Enhancer-binding protein β promotes pathogenesis of EAE.
abstract: The CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor is activated by multiple inflammatory stimuli, including IL-17 and LPS, and C/EBPβ itself regulates numerous genes involved in inflammation. However, the role of C/EBPβ in driving autoimmunity is not well understood. Here, we demonstrate that Cebpb-/-mice are resistant to EAE. Cebpb-/-mice exhibited reduced lymphocyte and APC infiltration into CNS following EAE induction. Furthermore, MOG-induced Th17 cytokine production was impaired in draining LN, indicating defects in Th17 cell priming. In vitro Th17 polarization studies indicated that T cell responses are not inherently defective, instead supporting the known roles for C/EBPβ in myeloid lineage cell activation as the likely mechanism for defective Th17 priming in vivo. However, we did uncover an unexpected role for C/EBPβ in regulating ll23r expression in APCs. ChIP assays confirmed that C/EBPβ binds directly to the Il23r gene promoter in dendritic cells and Th17 cells. These data establish C/EBPβ as a key driver of autoimmune inflammation in EAE, and propose a novel role for C/EBPβ in regulation of IL-23R expression.
authors.affiliation: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Simpson-Abelson
authors.affiliation: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Hernandez-Mir
authors.affiliation: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Childs
authors.affiliation: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J Agustin
authors.initials: JA
authors.lastname: Cruz
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pediatrics, Children's Hospital of UPMC, Pittsburgh, PA, USA.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Poholek
authors.affiliation: Molecular Biology Information Service, Health Sciences Library System, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ansuman
authors.initials: A
authors.lastname: Chattopadhyay
authors.affiliation: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: Sarah.Gaffen@pitt.edu.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
authors.affiliation: Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: Mmcgeach@pitt.edu.
authors.forename: Mandy J
authors.initials: MJ
authors.lastname: McGeachy
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; D016207:Cytokines; D018123:Receptors, Interleukin; C528688:interleukin-23 receptor, mouse
keywords: C/EBPβ; EAE; IL-17; IL-23R; Th17; Transcription factor