Sphingosine 1-phosphate (S1P) has been shown to be a bioactive lipid mediator intimately involved in mediating a variety of immunological processes. In particular, S1P regulates lymphocyte cell trafficking between the lymphatic system and the blood. The lysophospholipid signals mainly through five related G protein-coupled receptor subtypes, termed S1P(1) to S1P(5). S1P(1) 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 S1P levels in the serum and lymphatic organs. In addition to its direct effects on lymphocyte motility, S1P strengthens cell barrier integrity in sinus-lining endothelial cells, thereby reducing lymphocyte egress out of lymph nodes. Furthermore, S1P 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 S1P. After phosphorylation, FTY720 shares structural similarity with S1P, but in contrast to the natural ligand, phosphorylated FTY720 induces a prolonged internalization of S1P(1), resulting in an impaired S1P-mediated migration of lymphocytes.

Lysophosphatidic acid (LPA, 1-acyl-glycerol-3-phosphate) plays an important role in diverse biological responses including cell proliferation, differentiation, survival, migration, and tumor cell invasion. The most prominent source of LPA is platelets from which it is released after thrombin activation and is assumed to be an essential function of this lysophospholipid in cutaneous wound closure. Therefore, we examined the role of LPA on biological responses of keratinocytes. Although LPA potently enhances keratinocyte migration, it strongly induces growth arrest of proliferating epidermal cells. Thus, LPA possesses analogous actions to transforming growth factor-beta (TGF-beta), which is also released from degranulating platelets at wounded sites. In contrast to LPA, the intracellular signaling events of TGF-beta have been clearly identified and indicate that Smad3 is involved in chemotaxis and cell growth arrest of keratinocytes induced by this cytokine. Here we show that LPA, although it does not alter TGF-beta release is capable to activate Smad3 and results in a heteromerization with Smad4 and binding of the complex to its specific DNA-promoter elements. LPA completely fails to induce chemotaxis in Smad3-deficient cells, whereas growth inhibition is at least in part reduced. These findings indicate an essential role of Smad3 in diverse biological properties of LPA-stimulated keratinocytes.