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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 D3 [1,25(OH)2D3], 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)2D3 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)2D3 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)2D3/VDR, and a direct effect of 1,25(OH)2D3 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.
ACKNOWLEDGMENTS
We thank Milan Uskokovic (Hoffmann-LaRoche, Nutley, NJ) for providing 1,25(OH)2D3 and Puneet Dhawan and Anita Antes (UMDNJ, Newark, NS) for their assistance in certain aspects of this investigation. We acknowledge the assistance of Jessica Magid-Bernstein (Department of Neurology and Neurosciences, UMDNJ, Newark, NJ) with the human CD4+ T cell isolation and with the Runx1 siRNA experiments.
This work was supported by National Institutes of Health (NIH) grant DK-38961-22 to S.C., NIH grant NS55997 to L.S., NIH grant AR054389 to S.G., and NIH grant AI095055 to S.C. and L.S.