Although novel intracellular targets have also recently been identified. Studies using the S1PR agonist FTY720, which down-regulates S1PRs and induces lymphopenia, implicate the binding of S1P to its receptors in immune cell trafficking. In contrast, SK1 is implicated in the function of immune cells including cytokine production and chemotaxis in macrophages, oxidative burst and migration in neutrophils, and mast cell degranulation and migration. SK1 is highly regulated and has been shown to be BI-D1870 clinical trial activated by proinflammatory cytokines such as interleukin1 beta and tumor necrosis factor alpha both in vitro and in vivo. This activation by cytokines leads to induction of COX2 and production of prostaglandins. We have previously demonstrated that this pathway also occurs in vivo in an animal model of DSS-induced colitis and TNF-induced arthritis and that loss of SK1 prevents COX2 induction in both of these murine models of inflammation. There are two subclasses of IBD: ulcerative colitis and Crohn’s Disease. UC is restricted to mucosal inflammation in the colon, whereas CD can affect the entire gastrointestinal tract. Immunosuppressive agents have classically been utilized for the treatment of IBD; however, recent therapies have been developed to target more specific mediators of IBD, such as the increases in circulating and tissue TNFa. Previous studies, by our group and others, have demonstrated that pro-inflammatory cytokines such as TNFa can activate SK1 in cells and in vivo. Furthermore, we showed that total body genetic deletion of SK1 partially protected mice from DSS-induced colitis. Interestingly, genetic deletion of SK2 highlights opposing functions for the SK isoforms as loss of SK2 in both IBD and rheumatoid arthritis has been demonstrated to provide no protection from, and potentially worsen, inflammation or disease. Our previous study demonstrated an increase in SK1 expression in colon tissue from patients with ulcerative colitis. In addition, we observed an increase in SK1 expression and activity in colon tissue in DSS treated WT mice, as well as, an increase in S1P in circulation. SK12/2 DSS-treated mice were protected from both systemic inflammation and the local inflammatory response in colon tissue. However, by using the total body knockout we were unable to determine if tissue SK1/S1P were influencing the inflammatory response or if these factors were more important in the hematopoietic-derived cell population. In the current study we utilized bone marrow transplanted mice to determine the roles of each of these cell populations in DSS-induced colitis. Here we demonstrate distinct roles for SK1/S1P in the local and systemic inflammatory responses; where hematopoieticderived cells is critical for neutrophilia and extra-hematopoietic SK1 in colon epithelium is necessary for the COX2 expression in response to DSS-induced colitis. Sphingosine kinase 1 and S1P have been shown to play key roles in numerous inflammatory processes and disease states. Our previous results demonstrated that total body SK12/2 mice were partially protected from DSS-induced colitis.