[9, 10] Among many lipid mediators, S1P is essential for the trafficking and activation of immunocompetent cells.[11] S1P is a metabolite of sphingomyelin from both the host cell plasma

membrane and diet.[12] Sphingomyelin is degraded into ceramide by alkaline sphingomyelinase and subsequently to sphingosine by ceramidase. Sphingosine is then phosphorylated to generate S1P by sphingosine kinases.[11] S1P is formed in most cells, but is simultaneously irreversibly degraded by S1P lyase or dephosphorylated by S1P phosphatases.[11] Therefore, S1P levels are extremely low in most tissues but high in the blood and lymph because of the lack of S1P degrading INCB024360 clinical trial activity of erythrocytes, platelets, and lymphatic endothelial cells; the difference creates an S1P gradient between these types of tissues.[13, 14] Cells expressing S1P receptors sense the S1P gradient and traffic toward high concentrations of S1P. Among five closely related S1P receptors, the type 1 S1P

receptor (S1P1) is preferentially expressed by lymphocytes and thus determines lymphocyte emigration from and retention in the lymphoid tissue.[15] this website Naïve lymphocytes express high levels of S1P1, and their activation is associated with downregulation of this receptor. However, S1P1 expression recovers in fully differentiated activated lymphocytes. These dramatic changes in S1P1 determine whether the lymphocytes are retained in the lymphoid tissues or emigrate from them into the blood or lymph circulation. We and others have shown that S1P regulates the innate and acquired phases of gut immune responses and the development of intestinal immune diseases (reviewed

in Reference[12]). For instance, S1P regulates the trafficking of B cells in the PPs and subsequent intestinal IgA production.[16] In the PPs, B cells differentiate into IgA+ plasmablasts. During B cell differentiation in the PPs, the B cells change their expression of S1P1; high expression is noted on immunoglobulin M+ naïve B cells but is downregulated during class switching to IgA. The low level of S1P1 allows newly formed IgA+ B cells to be retained in the PPs so that they can differentiate into IgA+ plasmablasts. The IgA+ plasmablasts show recovery of S1P1 expression, MCE resulting in their emigration from the PPs.[16] In agreement with this finding, when mice were treated with the immunosuppressant FTY720 to induce downregulation of S1P1 expression,[17] IgA+ plasmablasts selectively accumulated in the PPs, and their population was decreased in the lamina propria.[16] As a result, FTY720-treated mice showed reduced intestinal IgA responses against orally administered protein Ag.[16] We have also reported that IgA PCs originated from peritoneal cavity, along with unique subsets of IELs require S1P for their trafficking into the intestine.