EDG6, a novel G-protein-coupled receptor related to receptors for bioactive lysophospholipids, is specifically expressed in lymphoid tissue

EDG receptors constitute a novel subfamily of G-protein-coupled receptors displaying a heterogeneous expression pattern. It was shown recently that the four members of this family thus far identified can bind lysophospholipids or lysosphingolipids as ligands. Here we report the identification and characterization of EDG6, a novel member of the EDG receptor family, isolated from in vitro differentiated human and murine dendritic cells. EDG6 is specifically expressed in fetal and adult lymphoid and hematopoietic tissue as well as in lung. The expression pattern of edg6 is strongly conserved in human and mouse. The human edg6 gene was mapped to chromosome 19p13.3 at the D19S120 marker. Considering the lymphoid-specific expression pattern of edg6 and the strong identity to the phospholipid-binding EDG receptor family, we propose that EDG6 may also act as a receptor for a lipid-derived ligand. Because of the known mitogenic and chemotactic activity of bioactive lipids, we believe that EDG6 may play an essential role in lymphocyte cell signaling

The sphingosine 1-phosphate receptor S1P4regulates cell shape and motility via coupling to Gi and G12/13

Sphingosine 1-phosphate (S1P) receptors represent a novel subfamily of G-protein-coupled receptors binding S1P specifically and with high affinity. Although their in vivo functions remain largely unknown, in vitro extracellular application of S1P induces distinct S1P receptor-dependent cellular responses including proliferation, differentiation, and migration. We have analyzed signaling pathways engaged by S1P4, which is highly expressed in the lymphoid system. Here we show that S1 P4 couples directly to Gαi and even more effectively to Gα12/13-subunits of trimeric G-proteins, but notto Gαq unlike other S1P receptors. Consequently, CHO-K1 cells ectopically expressing S1P4 potently activate the small GTPase Rho and undergo cytoskeletal rearrangements, inducing peripheral stress fiber formation and cell rounding, upon S1P stimulation. Overexpression of S1P4 in Jurkat T cells induces pertussis toxin-sensitive cell motility even in the absence of exogenously added S1P. In addition, S1P4 is internalized upon binding of S1P. The capacity of S1P4 to mediate cellular responses, such as motility and shape change through Gαi- and Gα12/13-coupled signaling pathways may be important for its in vivo function which is currently under investigation

Sphingosine-1-phospate receptor 4 (S1P4) deficiency profoundly affects dendritic cell function and TH17-cell differentiation in a murine model

Although predominantly expressed on lymphocytic and hematopoietic cells, the role of sphingosine-1-phospate receptor 4 (S1P(4)) in immune homeostasis is still poorly understood. In this report, we used a S1P(4)-deficient murine model to characterize the biological role of S1P(4)-mediated S1P signaling in the immune system. S1p(4)(-/-) animals showed normal peripheral lymphocyte numbers and a regular architecture of secondary lymphoid organs. Interestingly, S1P(4) only marginally affects T-cell function in vivo. In contrast, dendritic cell (DC) migration and cytokine secretion are profoundly affected by S1P(4) deficiency. Lack of S1P(4) expression on DCs significantly reduces T(H)17 differentiation of T(H) cells. Furthermore, in various in vivo models of T(H)1- or T(H)2-dominated immune reactions, S1P(4) deficiency consistently increased the amplitude of T(H)2-dominated immune responses, while those depending on T(H)1-dominated mechanisms were diminished. Finally, S1p(4)(-/-) mice showed decreased pathology in a model of dextran sulfate sodium-induced colitis. In summary, for the first time, we show that S1P(4) signaling is involved in the regulation of DC function and T(H)17 T-cell differentiation. S1P(4)-mediated S1P signaling also modifies the course of various immune diseases in a murine model. We propose that S1P(4) may constitute an interesting target to influence the course of various autoimmune pathologies