Sphingosine 1-phosphate and its G protein-coupled receptors constitute a multifunctional immunoregulatory system

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are distinctive mediators of immune cellular proliferation, survival and functions, which are present at highly active concentrations in blood, lymph, and tissue corridors of lymphocyte traffic [Moolenaar et al., 1997; Spiegel et al., 1998]. In the immune system, dendritic cells, macrophages, mast cells, and platelets are the principal sources of LPA and S1P. Each type of immune cell expresses a characteristic profile of one or more of the nine Edg-family G protein-coupled receptors (GPCRs) selective for either S1P or LPA, which is controlled developmentally and by diverse stimuli (Table I) [Goetzl et al., 2000; Chun et al., 2002]. S1P and, often less effectively, LPA are chemotactic for many types of immune cells, including T-cells, B-cells, dendritic cells, and NK cells at their normal ambient tissue levels of 3–300 nM [Zheng et al., 2000, 2001; Graeler et al., 2002; Idzko et al., 2002; Kveberg et al., 2002]. At blood and lymph concentrations of over 0.3–3 μM, however, S1P but not LPA nearly completely inhibits lymphocyte migration to chemokines and other stimuli, and suppresses less profoundly lymphocyte proliferation and secretion of some cytokines [Graeler et al., 2002; Dorsam et al., 2003]. That expression of LPA and S1P GPCRs in thymus is restricted to the last phases of development indicates possible roles in terminal differentiation and emigration of CD4 and CD8 T-cells, which remain to be elucidated definitively. As there are numerous and often redundant stimuli of T-cell migration and distinct immunological functions, but fewer specific suppressive influences, the immunoregulatory activities of S1P and its GPCRs are the principal focus of current interest. The potential importance of these immunoregulatory effects is emphasized by their magnitude and involvement in development, tissue distribution, and activities of lymphocytes. Some of the recent excitement in this field is also attributable to the strong possibility of discovering unique classes of immunoactive drugs that target S1P GPCRs. Newly established mouse genetic models of altered expression of T-cell S1P GPCRs and novel functional anti-S1P R monoclonal antibodies now have provided systems and reagents for analyzing further the separate immune contributions of each of the predominant T-cell S1P GPCRs. The results of such studies also may permit accurate predictions of the immune effects of individual S1P GPCR-selective agonists and antagonists. TABLE I Immune Cell Expression of mRNAs Encoding LPA and S1P GPCRs*