1,25-Dihydroxyvitamin D3 Ameliorates Th17 Autoimmunity via Transcriptional Modulation of Interleukin-17A
1,25-Dihydroxyvitamin D3 Ameliorates Th17 Autoimmunity via Transcriptional Modulation of Interleukin-17A
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DOI：
10.1128/mcb.05020-11
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发表时间：
2011-09-01
影响因子：
5.3
通讯作者：
Youssef, Sawsan
中科院分区：
文献类型：
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作者：
Joshi, Sneha;Pantalena, Luiz-Carlos;Youssef, Sawsan
一类新的炎性CD4(+)T细胞能产生白细胞介素17(IL-17)(称为Th17)，它在许多炎症条件和自身免疫性疾病中起关键作用。维生素D的活性形式1，25-二羟基维生素D-3[1，25(OH)(2)D-3]对人和小鼠T细胞中IL-17A的表达有直接的抑制作用。对患有实验性自身免疫性脑脊髓炎(EAE；多发性硬化症的小鼠模型)的小鼠进行体内治疗可以减少瘫痪和疾病的进展，并减少外周和中枢神经系统(CNS)中分泌IL-17A的CD4(+)T细胞。1，25(OH)(2)D-3抑制IL-17A表达的机制是由维生素D受体(VDR)介导的转录抑制。1，25(OH)(2)D-3对IL-17A的抑制作用包括阻断活化T细胞核因子(NFAT)、组蛋白脱乙酰基酶(HDAC)的募集、1，25(OH)(2)D-3/VDR对Run相关转录因子1(RUNX1)的截留以及1，25(OH)(2)D-3对Foxp3的直接诱导作用。我们的结果描述了有关维生素D和免疫系统的新机制和新概念，并提出了控制自身免疫性疾病的治疗目标。
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.