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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

The Interleukin-1-Converting Enzyme Inhibitor Pralnacasan Reduces Dextran Sulfate Sodium-Induced Murine Colitis and T Helper 1 T-Cell Activation

Division of Clinical Pharmacology (F.L., C.B., K.S., B.S., S.E., A.E.) and Section of Gastroenterology (N.L., M.D.), Medizinische Klinik Innenstadt of the University of Munich, Munich, Germany; Institute of Pathology, University of Mainz, Mainz, Germany (H.A.L.); and Aventis Pharma Deutschland GmbH, Frankfurt, Germany (M.S.)

The proinflammatory cytokines interleukin (IL)-1 and IL-18 are supposed to play a crucial role in the pathogenesis of human inflammatory bowel disease. To exert biological activity, the precursors of both IL-1 and IL-18 need to be cleaved by the interleukin-1-converting enzyme (ICE). IL-18 induces the synthesis of IFN- in T cells and NK cells. In the present study, we investigated the effect of the specific ICE inhibitor pralnacasan in dextran sulfate sodium-induced murine colitis. Colitis was induced in BALB/c mice by 3.5% dextran sulfate sodium dissolved in drinking water for 10 days. Pralnacasan was administered either intraperitoneally or orally every day. To assess in vivo efficacy, a clinical disease activity score was evaluated daily. Colon length, expression of IL-18 in colonic tissue, expression of interferon- (IFN-) in paraaortal lymphocytes, and systemic production of IFN- in splenocytes were analyzed post mortem. Intraperitoneally administered pralnacasan significantly reduced the clinical score compared with the dextran sulfate sodium control group from day 6 to day 10. Oral administration of pralnacasan also significantly reduced the clinical score at days 8 and 9. Administration of pralnacasan i.p. reduced the expression of intracolonic IL-18 significantly. Furthermore, pralnacasan reduced the number of IFN--positive lymphocytes in paraaortal lymph nodes. IFN- synthesis in stimulated splenocytes was significantly suppressed in all pralnacasan-treated groups. No side effects of pralnacasan were observed. In conclusion, pralnacasan is effective in the prevention of dextran sulfate sodium-induced colitis. This effect is probably mediated by suppression of the proinflammatory cytokines IL-18, IL-1, and IFN-.

Address correspondence to: Dr. Andreas Eigler, Division of Clinical Pharmacology, University of Munich, Ziemssenstrae 1, 80336 München, Germany. E-mail: andreas.eigler{at}med.uni-muenchen.de

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