RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 583
OP 590
DO 10.1124/jpet.103.057059
VO 308
IS 2
A1 Florian Loher
A1 Christian Bauer
A1 Nikola Landauer
A1 Kathrin Schmall
A1 Britta Siegmund
A1 Hans Anton Lehr
A1 Marc Dauer
A1 Martin Schoenharting
A1 Stefan Endres
A1 Andreas Eigler
YR 2004
UL http://jpet.aspetjournals.org/content/308/2/583.abstract
AB 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