title: 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A.
abstract: A new class of inflammatory CD4(+) T cells that produce interleukin-17 (IL-17) (termed Th17) has been identified, which plays a critical role in numerous inflammatory conditions and autoimmune diseases. The active form of vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], has a direct repressive effect on the expression of IL-17A in both human and mouse T cells. In vivo treatment of mice with ongoing experimental autoimmune encephalomyelitis (EAE; a mouse model of multiple sclerosis) diminishes paralysis and progression of the disease and reduces IL-17A-secreting CD4(+) T cells in the periphery and central nervous system (CNS). The mechanism of 1,25(OH)(2)D(3) repression of IL-17A expression was found to be transcriptional repression, mediated by the vitamin D receptor (VDR). Transcription assays, gel shifting, and chromatin immunoprecipitation (ChIP) assays indicate that the negative effect of 1,25(OH)(2)D(3) on IL-17A involves blocking of nuclear factor for activated T cells (NFAT), recruitment of histone deacetylase (HDAC), sequestration of Runt-related transcription factor 1 (Runx1) by 1,25(OH)(2)D(3)/VDR, and a direct effect of 1,25(OH)(2)D(3) on induction of Foxp3. Our results describe novel mechanisms and new concepts with regard to vitamin D and the immune system and suggest therapeutic targets for the control of autoimmune diseases.
authors: Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA.
authors: Sneha
authors: S
authors: Joshi
authors: Luiz-Carlos
authors: LC
authors: Pantalena
authors: Xikui K
authors: XK
authors: Liu
authors: Sarah L
authors: SL
authors: Gaffen
authors: Hong
authors: H
authors: Liu
authors: Christine
authors: C
authors: Rohowsky-Kochan
authors: Kenji
authors: K
authors: Ichiyama
authors: Akihiko
authors: A
authors: Yoshimura
authors: Lawrence
authors: L
authors: Steinman
authors: Sylvia
authors: S
authors: Christakos
authors: Sawsan
authors: S
authors: Youssef
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018167:Receptors, Calcitriol / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology
chemical_list: D020381:Interleukin-17; D018167:Receptors, Calcitriol; D014815:Vitamins; C118756:dihydroxy-vitamin D3; D014807:Vitamin D