Crohn’s & Colitis Congress™

P002 - 2-ACCETYL-4-TETRAHYDROXYBUTYL IMIDAZOLE AMELIORATES DEXTRAN SULFATE SODIUM-INDUCED COLITIS VIA SUPPRESSION OF SPHINGOSINE-1-PHOSPHATE LYASE

19 Jan 18
5:30 PM - 7:00 PM

Tracks: Clinical and Research Challenges, Poster Session

Speaker(s): Kazuhiko Shirakabe, Assistant professor, Department of Internal Medicine, National Defense Medical College

Background: In the field of inflammatory bowel diseases (IBD), a variety of drug trials targeting on lymphocyte migration got hot during recent years. FTY720, sphingosine-1-phosphate (S1P) agonist is also targeting S1P receptor on naïve lymphocyte. 2-accetyl-4-tetrahydroxybutyl imidazole (THI) works as an inhibitor of S1P lyase (SPL) and suggests possible immunomodulatory effect. However, whether SPL inhibitor ameliorates colitis or how it works in intestinal immune system have not been clarified. We aimed to reveal the effect of THI on colitis model and the mechanism of action in intestinal immune system regarding lymphocyte migration. Methods: Study1: Male C57BL/6J mice were treated with 3% dextran sulfate sodium (DSS) was given in the drinking water. In some experiment, mice were pretreated with THI (50mg/L). We investigated clinical score, histological score and inflammatory gene expression. Study2: Male Wistar rats were used to observe dynamics of lymphocyte migration in Peyer’s patches (PPs). Fluorescently labeled lymphocytes from intestinal lymph were injected into jugular vein of recipient rat to observe microcirculation in PPs. We observed it continuously by a confocal laser scanning microscope and recorded it for several hours in manner of time-lapse photography. The effect of THI and FTY720 were analyzed. Results: Study1: THI significantly ameliorated DSS-induced colitis clinically and histologically. THI decreased colonic lymphocyte infiltration and expression of mucosal proinflammatory cytokines. Study2: Lymphocytes attached to high endothelial venules (HEVs) and migrated in stroma to lymph capillaries under rat physiological condition. THI and FTY720 suppressed egression from HEVs. Conclusion: This is the first study unraveling one of the mechanisms how THI ameliorated DSS-induced colitis by direct intravital observation. SPL inhibitor like THI might become a novel immunosuppressant for IBD therapy.