Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720
Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720
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DOI：
10.1074/jbc.m506293200
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发表时间：
2005-11-04
影响因子：
4.8
通讯作者：
Lynch, KR
中科院分区：
文献类型：
--
作者：
Kharel, Y;Lee, S;Lynch, KR
模拟鞘氨醇1-磷酸(S1P)的免疫治疗药物扰乱淋巴细胞运输，使T辅助细胞和T效应细胞保留在次级淋巴组织中，远离炎症部位。典型的治疗药物2-烷基-2-氨基-1，3-丙二醇(FTY720)只有在被一个或多个未知的激酶磷酸化后才能刺激S1P信号通路。我们产生了鞘氨醇激酶2(SPHK2)缺失的小鼠，以证明该激酶负责FTY720的磷酸化，从而对免疫系统产生后续的作用。SPHK2的全身来源和淋巴细胞定位来源均与FTY720诱导的淋巴细胞减少有关。虽然FTY720在体内被SPHK2选择性地激活，但其他S1P前体药物可以通过额外的鞘氨醇激酶的作用而被磷酸化而导致淋巴细胞减少。我们的结果强调了SPHK2在淋巴细胞和其他组织中的表达对于免疫调节和药物代谢的重要性。
Immunotherapeutic drugs that mimic sphingosine 1-phosphate (S1P) disrupt lymphocyte trafficking and cause T helper and T effector cells to be retained in secondary lymphoid tissue and away from sites of inflammation. The prototypical therapeutic agent, 2-alkyl-2-amino-1,3-propanediol (FTY720), stimulates S1P signaling pathways only after it is phosphorylated by one or more unknown kinases. We generated sphingosine kinase 2 (SPHK2) null mice to demonstrate that this kinase is responsible for FTY720 phosphorylation and thereby its subsequent actions on the immune system. Both systemic and lymphocyte-localized sources of SPHK2 contributed to FTY720 induced lymphopenia. Although FTY720 was selectively activated in vivo by SPHK2, other S1P pro-drugs can be phosphorylated to cause lymphopenia through the action of additional sphingosine kinases. Our results emphasize the importance of SPHK2 expression in both lymphocytes and other tissues for immune modulation and drug metabolism.