Aside from all targets S1P1 signaling, other factors could contribute to the beneficial effect of FTY720 in the cupr model, including glioprotection via S1P5 signaling in OLGs and indirect or anti-inflammatory actions of FTY720 on astrocytes and microglia. In summary, we have provided evidence for a protective effect of FTY720 in the cupr model, which is independent of its action on lymphocyte trafficking; and a potential role of S1P1 in OLG lineage cells in regulating myelination and the response to injury. Compared to other immunomodulatory agents in MS therapy, FTY720 is unique in its neurobiological effects, which may translate to slowing of disease progression. Indeed, FTY720 not only reduces relapse rate, but also decreases the cumulative probability of disability progression in MS (6).

A solely anti-inflammatory action of FTY720 would have led to the so called pseudoatrophy in brain MRI during the first year of treatment due to a reduction of water content, but this was not observed in the case of FTY720. Our results suggest that the best strategy for initiating treatment with FTY720 would be prior to or at the onset of insult (e.g., in between MS exacerbations or during disease quiescence). During MS relapse, FTY720 may augment astrogliosis once an injury response has occurred. Overall, our data support the concept that S1P receptors expressed by neuroglia are potential target for drug development that may have a wide therapeutic applications. Supplementary Material Supplemental Data: Click here to view. Acknowledgments The authors thank Dr. B. Popko, Dr. N. Turgut, Dr.

T. Johnson, and B. Durafourt for their assistance or advice in some experiments. This work was supported by the U.S. National Institute of Neurological Disorders and Stroke (R21 NS049014), the National MS Society (RG3951A7/1), and a gift from M. P. Miller (B.S.); the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (R.L.P.); the National MS Society (TR3762-A-1), a grant from the MS Society of Canada, and a grant from Novartis (J.P.A.); and a Canadian Institutes of Health Research studentship (V.E.M.). Footnotes This article includes supplemental data. Please visit http://www.fasebj.org to obtain this information.

cholangiocarcinoma (cca) is a devastating malignancy of intrahepatic and extrahepatic bile ducts, which is steadily increasing worldwide in incidence, morbidity, and mortality (3, 8). CCA is often clinically silent until it becomes an advanced disease with obstructive symptoms (2, 46). The response of this neoplasm to conventional chemotherapy is poor, with surgical resection being AV-951 the only effective therapeutic approach, but, unfortunately, applicable only to a minority of patients (46).