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      1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A.

      Molecular and Cellular Biology
      Amino Acid Sequence, Animals, Autoimmunity, drug effects, immunology, Blotting, Western, CD4-Positive T-Lymphocytes, metabolism, Cell Line, Tumor, Chromatin Immunoprecipitation, Encephalomyelitis, Autoimmune, Experimental, prevention & control, Female, HEK293 Cells, Humans, Interleukin-17, genetics, Jurkat Cells, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Transgenic, Molecular Sequence Data, Receptors, Calcitriol, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Th17 Cells, Transcription, Genetic, Vitamin D, analogs & derivatives, pharmacology, Vitamins

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          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.

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