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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Florian Loher, Christian Bauer, Nikola Landauer, Kathrin Schmall, Britta Siegmund, Hans Anton Lehr, Marc Dauer, Martin Schoenharting, Stefan Endres and Andreas Eigler
Journal of Pharmacology and Experimental Therapeutics February 2004, 308 (2) 583-590; DOI: https://doi.org/10.1124/jpet.103.057059
Florian Loher
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Christian Bauer
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Nikola Landauer
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Kathrin Schmall
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Britta Siegmund
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Hans Anton Lehr
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Marc Dauer
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Martin Schoenharting
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Stefan Endres
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Andreas Eigler
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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

  • This work was supported by Aventis Deutschland GmbH (Frankfurt, Germany) and Vertex Inc., Paramus, NJ.

  • DOI: 10.1124/jpet.103.057059.

  • 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.

  • ↵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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Journal of Pharmacology and Experimental Therapeutics: 308 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 2
1 Feb 2004
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Florian Loher, Christian Bauer, Nikola Landauer, Kathrin Schmall, Britta Siegmund, Hans Anton Lehr, Marc Dauer, Martin Schoenharting, Stefan Endres and Andreas Eigler
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 583-590; DOI: https://doi.org/10.1124/jpet.103.057059

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Florian Loher, Christian Bauer, Nikola Landauer, Kathrin Schmall, Britta Siegmund, Hans Anton Lehr, Marc Dauer, Martin Schoenharting, Stefan Endres and Andreas Eigler
Journal of Pharmacology and Experimental Therapeutics February 1, 2004, 308 (2) 583-590; DOI: https://doi.org/10.1124/jpet.103.057059
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