TY - JOUR
T1 - 1,25-Dihydroxyvitamin D 3 ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A
AU - Joshi, Sneha
AU - Pantalena, Luiz Carlos
AU - Liu, Xikui K.
AU - Gaffen, Sarah L.
AU - Liu, Hong
AU - Rohowsky-Kochan, Christine
AU - Ichiyama, Kenji
AU - Yoshimura, Akihiko
AU - Steinman, Lawrence
AU - Christakos, Sylvia
AU - Youssef, Sawsan
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80052387833&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052387833&partnerID=8YFLogxK
U2 - 10.1128/MCB.05020-11
DO - 10.1128/MCB.05020-11
M3 - Article
C2 - 21746882
AN - SCOPUS:80052387833
SN - 0270-7306
VL - 31
SP - 3653
EP - 3669
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 17
ER -
