The role of the lysophospholipid sphingosine 1-phosphate in immune cell biology

Sphingosine I-phosphate (SIP) has been shown to be a bioactive lipid mediator intimately involved in mediating a variety of immunological processes. In particular, SIP regulates lymphocyte cell trafficking between the lymphatic system and the blood. The lysophospholipid signals mainly through five related G protein-coupled receptor subtypes, termed SIP, to SIP,. SIP, seems to play an essential role in cell trafficking, as this receptor subtype promotes the egress of T and B cells from secondary lymphatic organs. This S1P(1)-mediated migratory response is a consequence of different SIP levels in the serum and lymphatic organs. In addition to its direct effects on lymphocyte motility, SIP strengthens cell barrier integrity in sinus-lining endothelial cells, thereby reducing lymphocyte egress out of lymph nodes. Furthermore, SIP modulates cytokine profiles in T and dendritic cells, resulting in an elevated differentiation of T helper-2 cells during the T cell activation process. It is of interest that the mode of molecular action of the novel immunomodulator FTY720 interferes with the signaling of SIP. After phosphorylation, FFY720 shares structural similarity with SIP, but in contrast to the natural ligand, phosphorylated FTY720 induces a prolonged internalization of SIP,, resulting in an impaired S1P-mediated migration of lymphocytes.