Abstract
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.
Footnotes
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This work was supported by Aventis Deutschland GmbH (Frankfurt, Germany) and Vertex Inc., Paramus, NJ.
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DOI: 10.1124/jpet.103.057059.
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ABBREVIATIONS: CD, Crohn's disease; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; Th1, T helper 1; IBD, inflammatory bowel disease; IL, interleukin; ICE, interleukin-1β-converting enzyme; PMA, phorbol 12-myristate 13-acetate; HEC, hydroxyethylcellulose; ELISA, enzyme-linked immunosorbent assay; FACS, fluorescence-activated cell sorting.
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↵1 These authors contributed equally to this work.
- Received July 26, 2003.
- Accepted October 28, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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