TY - JOUR T1 - The Interleukin-1β-Converting Enzyme Inhibitor Pralnacasan Reduces Dextran Sulfate Sodium-Induced Murine Colitis and T Helper 1 T-Cell Activation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 583 LP - 590 DO - 10.1124/jpet.103.057059 VL - 308 IS - 2 AU - Florian Loher AU - Christian Bauer AU - Nikola Landauer AU - Kathrin Schmall AU - Britta Siegmund AU - Hans Anton Lehr AU - Marc Dauer AU - Martin Schoenharting AU - Stefan Endres AU - Andreas Eigler Y1 - 2004/02/01 UR - http://jpet.aspetjournals.org/content/308/2/583.abstract N2 - The proinflammatory cytokines interleukin (IL)-1β 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-1β and IL-18 need to be cleaved by the interleukin-1β-converting enzyme (ICE). IL-18 induces the synthesis of IFN-γ 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-γ (IFN-γ) in paraaortal lymphocytes, and systemic production of IFN-γ 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-γ-positive lymphocytes in paraaortal lymph nodes. IFN-γ 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-1β, and IFN-γ. The American Society for Pharmacology and Experimental Therapeutics ER -