1,25-Dihydroxyvitamin D 3 Ameliorates Th17 Autoimmunity via Transcriptional Modulation of Interleukin-17A

Abstract

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.