1磷酸鞘氨醇及其G蛋白偶联受体的免疫调节功能研究进展

1磷酸鞘氨醇（sphingosine—l—phosphate，S1P）是一种具有重要生物学活性的溶血磷脂，它作为第一信使与各种免疫细胞膜上相应的G蛋白偶联受体相互作用发挥不同的免疫调节功能。S1P可抑制T细胞的增殖，并抑制活化的CD4^＋ T细胞分泌IFN-γ和IL-4。SIP对T细胞、B细胞、树突状细胞和NK细胞都具有趋化性，其主要效应是通过其受体SIP1介导调节淋巴细胞再循环和组织分布。S1P对调节性T细胞趋化性弱，是调节性T细胞发挥最佳活性所必需的。新型免疫抑制剂FFY720进入人体后快速磷酸化，形成具有生物学活性的FFY720-P，与SIP相似，是其受体S1P1、S1P3、S1P。和S1P，的真正激动剂，可影响成熟T细胞、B细胞、树突状细胞及调节性T细胞的组织分布与功能活性，具有低毒高效可逆的免疫抑制效应，能够预防异体移植物排斥及治疗自身免疫病。本文就S1P的合成、代谢及其G蛋白偶联受体在免疫细胞的表达、对各种免疫细胞的影响、以S1PGPCRs为靶点的药物及其临床意义进行综述。

Regulation of Immunity by Sphingosine 1-phosphate and Its G Proteincoupled Receptors——Review

Sphingosine 1-phosphate (S1P) is an important biologically active lysophospholipid that transmits signals through a family of G-protein-coupled receptors (GPCRs) to regulate the vital functions of several types of immune cells. The S1P GPCRs suppress both generation of specialized functional cytokines, such as IFN-gamma and IL-4, and proliferation of T-cells. Although S1P is chemotactic to T cells, B cells, dendritic cells, and natural killer cells, the major effect of S1P on the immune system is the regulation of lymphocyte recirculation and tissue distribution by S1P and S1P1. Chemotactic response of CD4+CD25+ regulatory T cells to S1P is reduced, but its optimal suppressive activities require S1P. FTY720, a new class of immunomodulator, is rapidly phosphorylated by sphingosine kinase 2 in vivo to form the biologically active phosphorylated-FTY720 (FTY720-P), which closely resembles S1P. The FTY720-P is a true agonist for S1P1, S1P3, S1P4, and S1P5, it affects the tissue distribution and functional activity of T cells, B cells, dendritic cells and regulatory T cells. FTY720 were demonstrated to be a hypotoxic, great effective and reversible immunosuppressive efficacy to prevent allograft rejection and treat some autoimmune diseases. In this article, the synthesis and metabolism of S1P, the expression of S1P GPCRs in immune cells, the effect of S1P on immune cells, the drugs targeted to S1P GPCRs and their clinical implications are reviewed.