1,25-Dihydroxyvitamin D 3 ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A

Sneha Joshi, Luiz Carlos Pantalena, Xikui K. Liu, Sarah L. Gaffen, Hong Liu, Christine Rohowsky-Kochan, Kenji Ichiyama, Akihiko Yoshimura, Lawrence Steinman, Sylvia Christakos, Sawsan Youssef

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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) 2D 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) 2D 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) 2D 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) 2D 3/VDR, and a direct effect of 1,25(OH) 2D 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.

Original languageEnglish
Pages (from-to)3653-3669
Number of pages17
JournalMolecular and Cellular Biology
Volume31
Issue number17
DOIs
Publication statusPublished - 2011 Sep 1

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Joshi, S., Pantalena, L. C., Liu, X. K., Gaffen, S. L., Liu, H., Rohowsky-Kochan, C., Ichiyama, K., Yoshimura, A., Steinman, L., Christakos, S., & Youssef, S. (2011). 1,25-Dihydroxyvitamin D 3 ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Molecular and Cellular Biology, 31(17), 3653-3669. https://doi.org/10.1128/MCB.05020-11