title: CCAAT/enhancer binding protein-δ expression by dendritic cells regulates CNS autoimmune inflammatory disease.
abstract: CCAAT enhancer binding protein-delta (C/EBPδ) is a transcription factor that regulates inflammatory processes mediating bystander neuronal injury and CNS autoimmune inflammatory disease. The mechanism of the involvement of C/EBPδ in these processes remains to be determined. Here, we examined the cellular source(s) and mechanisms by which C/EBPδ may be involved in an animal model of multiple sclerosis. Mice deficient in C/EBPδ expression exhibited less severe clinical disease than wild-type littermates in response to induction of experimental autoimmune encephalomyelitis (EAE) by vaccination with a myelin oligodendrocyte glycoprotein (MOG) fragment. This reduction in EAE severity was associated with a significant alteration in the complement of major CNS T-helper (Th) cell subtypes throughout disease, manifest as reduced ratios of Th17 cells to regulatory T-cells (Tregs). Studies in bone marrow chimeric mice indicated that C/EBPδ expression by peripherally derived immune cells mediates C/EBPδ involvement in EAE. Follow up in vitro and in vivo examination of dendritic cell (DC) mediated Th-cell development suggests that C/EBPδ suppresses DC expression of interleukin-10 (IL-10), favoring Th17 over Treg development. In vitro and in vivo blockade of IL-10 signaling attenuated the effect of reduced C/EBPδ expression by DCs on Th17:Treg ratios. These findings identify C/EBPδ as an important DC transcription factor in CNS autoimmune inflammatory disease by virtue of its capacity to alter the Th17:Treg balance in an IL-10 dependent fashion.
authors: Laboratory of Neuroinflammation, Inflammation Research Program, St Vincent's Centre for Applied Medical Research, St Vincent's Hospital and University of New South Wales, Sydney 2010, New South Wales, Australia.
authors: Vicky W W
authors: VW
authors: Tsai
authors: Mohammad G
authors: MG
authors: Mohammad
authors: Ornella
authors: O
authors: Tolhurst
authors: Samuel N
authors: SN
authors: Breit
authors: Paul E
authors: PE
authors: Sawchenko
authors: David A
authors: DA
authors: Brown
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018992:Myelin-Associated Glycoprotein / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018992:Myelin-Associated Glycoprotein; D016753:Interleukin-10; D051743:CCAAT-Enhancer-Binding Protein-delta