1,25 dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNγ axis leading to Th1 response in experimental allergic encephalomyelitis
1,25 dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNγ axis leading to Th1 response in experimental allergic encephalomyelitis
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DOI：
10.1002/jnr.20826
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发表时间：
2006-05-15
影响因子：
4.2
通讯作者：
Bright, John J.
中科院分区：
文献类型：
--
作者：
Muthian, Gladson;Raikwar, Himanshu P.;Bright, John J.
实验性变态反应性脑脊髓炎（EAE）是一种Th 1细胞介导的多发性硬化症（MS）自身免疫性疾病模型。维生素D缺乏通常在MS患者中观察到，维生素D补充剂可减轻EAE和MS的临床症状。早期研究表明，用维生素D类似物进行体内治疗可改善EAE，并抑制IL-12产生和Th 1分化。然而，维生素D在EAE/MS中调节Th 1应答的机制尚不清楚。我们表明C57 BL/6和SJL/J小鼠的体内治疗（i. p.）从第0-30天每隔一天用100 ng 1，25-二羟基维生素D3治疗，与IL-12产生和神经抗原特异性Th 1应答的抑制相关地改善EAE。在EOC-20小胶质细胞中，用1，25（OH）2D 3体外处理抑制IFN γ诱导的STAT 1酪氨酸磷酸化，而不影响JAK 2。用1，25（OH）2D 3处理活化的T细胞还抑制IL-12诱导的JAK 2、TYK 2、STAT 3和STAT 4的酪氨酸磷酸化，这与体外T细胞增殖的降低有关。这些发现强调了维生素D调节IL-12/IFN γ轴中的JAK-STAT信号通路导致Th 1分化的事实，并进一步表明其在MS和其他Th 1细胞介导的自身免疫性疾病的治疗中的用途。(c)2006威利-利斯公司
Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). Vitamin D deficiency is commonly observed in MS patients and vitamin D supplements reduce the clinical symptoms of EAE and MS. Earlier studies have shown that in vivo treatment with vitamin D analogs ameliorates EAE in association with the inhibition of IL-12 production and Th1 differentiation. The mechanisms in the regulation of Th1 response by vitamin D in EAE/MS are, however, not known. We show that in vivo treatment of C57BL/6 and SJL/J mice (i.p.) with 100 ng of 1,25 dihydroxyvitamin D3, on every other day from Day 0-30, ameliorates EAE in association with the inhibition of IL-12 production and neural antigen-specific Th1 response. In vitro treatment with 1,25(OH)2D3 inhibited IFN gamma-induced tyrosine phosphorylation of STAT1, without affecting JAK2, in EOC-20 microglial cells. Treatment of activated T cells with 1,25(OH)2D3 also inhibited the IL-12-induced tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 in association with a decrease in T cell proliferation in vitro. These findings highlight the fact that vitamin D modulates JAK-STAT signaling pathway in IL-12/IFN gamma axis leading to Th1 differentiation and further suggest its use in the treatment of MS and other Th1 cell-mediated autoimmune diseases. (c) 2006 Wiley-Liss, Inc.