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摘要:
Infiltration of myelin-specific helper T (Th) cells into the central nervous system (CNS) plays a key role in pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the involvement of sphingosine 1-phosphate (S1P)-S1P receptor 1 (S1P1) axis in lymphocytes for EAE development when C57BL/6 mice were immunized with myelin oliogodendrocyte glycoprotein (MOG). The expression of S1P1 mRNA and S1P responsiveness of lymphocytes in draining lymph nodes (DLN) were down-regulated markedly after MOG immunization until onset of EAE. Accompanying with reacquisition of down-regulated S1P1 transcript and S1P responsiveness in DLN lymphocytes, MOG-immunized mice developed EAE symptoms with significant infiltration of Th1 and Th17 cells into the CNS and a marked elevation of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Prophylactic administration of an S1P1 functional antagonist, fingolimod hydrochloride (FTY720, 0.3 mg/kg, orally) significantly inhibited EAE development and almost completely prevented infiltration of Th1 and Th17 cells into the CNS with a marked reduction of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Similar results were obtained by treatment with an S1P1-selective agonist, SEW2871 or an S1P lyase inhibitor, 2-acetyl-4-tetrahydroxybutylimidazole. Moreover, FTY720-phosphate and SEW2871 inhibited in vitro migration of Th1 and Th17 cells toward S1P but did not affect cytokine production or generation of Th1 or Th17 cells. These results suggest that reacquisition of S1P1 expression in DLN lymphocytes plays a major role in trafficking of myelin antigen-specific Th1/Th17 cells from DLN to the CNS in EAE and that prophylactic effect of FTY720 on EAE is predominantly caused by functional antagonism via lymphocytic S1P1.
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篇名 Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —I
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 Th1 CELLS Th17 CELLS
年,卷(期) ylyzyyw_2013,(8) 所属期刊栏目
研究方向 页码范围 628-637
页数 10页 分类号 R73
字数 语种
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节点文献
SPHINGOSINE
1-Phosphosphate
RECEPTOR
1
FINGOLIMOD
Hydrochloride
(FTY720)
Experimental
Autoimmune
ENCEPHALOMYELITIS
Th1
CELLS
Th17
CELLS
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
论文1v1指导