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摘要:
Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. However, this treatment showed an only partial inhibition of Th1/Th17 cell infiltration into the central nervous system (CNS), suggesting that down-regulation of lymphocytic S1P1 is insufficient to explain the therapeutic effect of FTY720 on EAE. On the other hand, the therapeutic administration of FTY720 reduced the mRNA expressions of IL-6, CCL2, and glial fibrillary acidic protein, an activation marker of astrocytes, in the CNS of EAE mice. In human astrocytic glyoma, U373MG cells, mRNA expression of S1P1 was higher as compared with those of the other S1P receptor subtypes and phosphorylation of Akt was induced by S1P, FTY720-phosphate (FTY720-P), or an S1P1-selective agonist, SEW2871. FTY720-P appeared to induce down-regulation of S1P1 in U373MG cells, implying a functional antagonism at S1P1 on astrocytes. S1P but not FTY720-P induced production of IL-6, IL-8, and CCL2 significantly and treatment with FTY720-P or SEW2871 inhibited production of these pro-inflammatory cytokines from U373MG cells stimulated with S1P. These results suggest that S1P-S1P1 axis induces production of pro-inflammatory cytokines by astrocytes. Consequently, it is highly probable that the therapeutic effects of FTY720 on EAE are caused by inhibiting not only egress of myelin-specific Th cells from the draining lymph nodes but also activation of astrocytes in the CNS.
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篇名 Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —II
来源期刊 药理与制药(英文) 学科 医学
关键词 SPHINGOSINE 1-Phosphosphate RECEPTOR 1 FINGOLIMOD Hydrochloride (FTY720) Experimental Autoimmune ENCEPHALOMYELITIS Astrocytes PRO-INFLAMMATORY Cytokines
年,卷(期) ylyzyyw_2013,(8) 所属期刊栏目
研究方向 页码范围 638-646
页数 9页 分类号 R73
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研究主题发展历程
节点文献
SPHINGOSINE
1-Phosphosphate
RECEPTOR
1
FINGOLIMOD
Hydrochloride
(FTY720)
Experimental
Autoimmune
ENCEPHALOMYELITIS
Astrocytes
PRO-INFLAMMATORY
Cytokines
研究起点
研究来源
研究分支
研究去脉
引文网络交叉学科
相关学者/机构
期刊影响力
药理与制药(英文)
月刊
2157-9423
武汉市江夏区汤逊湖北路38号光谷总部空间
出版文献量(篇)
444
总下载数(次)
0
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