Gräler Markus H
Institute for Immunology, Hannover Medical School, Hannover, Germany.
Cell Physiol Biochem. 2010;26(1):79-86. doi: 10.1159/000315108. Epub 2010 May 18.
Sphingosine 1-phosphate (S1P) is an important regulator of many different immune functions including lymphocyte circulation, antigen presentation, and T cell development. It stimulates five G protein-coupled receptors designated S1P(1-5), which are also expressed by immune cells. S1P receptors couple to different heterotrimeric G proteins including G alpha i, q, and 12/13, and elicit cellular signalling events by activating the small GTPases Rac and Rho and protein kinases Akt, ERK, and JNK, and by inducing cellular calcium flux and inhibiting cAMP accumulation, amongst others. S1P is the exit signal for lymphocytes leaving lymphoid organs and present in blood and lymph at high nanomolar concentrations due to the S1P-producing activity of sphingosine kinases (SK). The S1P-degrading enzyme S1P-lyase maintains low amounts of S1P in lymphoid organs. Disrupting this concentration difference by S1P receptor agonists and antagonists like FTY720, SEW2871, and VPC23019, by an anti-S1P antibody, or by inhibiting the S1P-lyase has therapeutic potential for autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis and for many other disorders like cancer, fibrosis, inflammation, macular degeneration, diabetic retinopathy, and glaucoma. This report aims to provide a brief overview of concepts, approaches, pharmaceutical compounds, and targets that are currently used to modulate S1P-driven immune functions.
1-磷酸鞘氨醇（S1P）是多种不同免疫功能的重要调节因子，包括淋巴细胞循环、抗原呈递和T细胞发育。它可激活五种名为S1P(1 - 5)的G蛋白偶联受体，免疫细胞也表达这些受体。S1P受体与不同的异源三聚体G蛋白偶联，包括Gαi、q和12/13，并通过激活小GTP酶Rac和Rho以及蛋白激酶Akt、ERK和JNK，诱导细胞钙通量和抑制cAMP积累等方式引发细胞信号事件。S1P是淋巴细胞离开淋巴器官的输出信号，由于鞘氨醇激酶（SK）的S1P生成活性，其在血液和淋巴中的浓度高达纳摩尔水平。S1P降解酶S1P裂解酶维持淋巴器官中低水平的S1P。通过FTY720、SEW2871和VPC23019等S1P受体激动剂和拮抗剂、抗S1P抗体或抑制S1P裂解酶来破坏这种浓度差异，对于自身免疫性疾病如多发性硬化症（MS）和类风湿性关节炎以及许多其他疾病如癌症、纤维化、炎症、黄斑变性、糖尿病视网膜病变和青光眼具有治疗潜力。本报告旨在简要概述目前用于调节S1P驱动的免疫功能的概念、方法、药物化合物和靶点。
