The immune modulator FTY720 targets sphingosine 1-phosphate receptors
The immune modulator FTY720 targets sphingosine 1-phosphate receptors
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DOI：
10.1074/jbc.c200176200
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发表时间：
2002-06-14
影响因子：
4.8
通讯作者：
Lynch, KR
中科院分区：
文献类型：
--
作者：
Brinkmann, V;Davis, MD;Lynch, KR
免疫抑制药物如环孢菌素使器官移植得以广泛开展，但其应用因毒性而受限，并且在自身免疫性疾病（如多发性硬化症）的慢性治疗中无效。相比之下，免疫调节药物FTY720在多种移植和自身免疫模型中有效，不会诱导全身性免疫抑制状态，且在人类肾移植中有效。FTY720会引发淋巴细胞减少，这是由于淋巴细胞通过未知机制从循环可逆地重新分布到次级淋巴组织所致。利用FTY720及其几种类似物，我们现在表明FTY720可被鞘氨醇激酶磷酸化；磷酸化化合物是四种1 - 磷酸鞘氨醇受体的强效激动剂，并且在多发性硬化症的啮齿动物模型中代表了治疗原理。我们的研究结果表明，FTY720磷酸化后通过1 - 磷酸鞘氨醇信号通路来调节趋化反应和淋巴细胞运输。
Immunosuppressant drugs such as cyclosporin have allowed widespread organ transplantation, but their utility remains limited by toxicities, and they are ineffective in chronic management of autoimmune diseases such as multiple sclerosis. In contrast, the immune modulating drug FTY720 is efficacious in a variety of transplant and autoimmune models without inducing a generalized immunosuppressed state and is effective in human kidney transplantation. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms. Using FTY720 and several analogs, we show now that FTY720 is phosphorylated by sphingosine kinase; the phosphorylated compound is a potent agonist at four sphingosine 1-phosphate receptors and represents the therapeutic principle in a rodent model of multiple sclerosis. Our results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.