Article: article from journal or magazin.
The interleukin-1 beta-converting enzyme inhibitor pralnacasan reduces dextran sulfate sodium-induced murine colitis and T helper 1 T-cell activation.
Journal of Pharmacology and Experimental Therapeutics
The proinflammatory cytokines interleukin (IL)-1beta 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-1beta and IL-18 need to be cleaved by the interleukin-1beta-converting enzyme (ICE). IL-18 induces the synthesis of IFN-gamma 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-gamma (IFN-gamma) in paraaortal lymphocytes, and systemic production of IFN-gamma 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-gamma-positive lymphocytes in paraaortal lymph nodes. IFN-gamma 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-1beta, and IFN-gamma.
Animals, Azepines/pharmacology, Azepines/therapeutic use, Caspase 1/antagonists & inhibitors, Colitis/chemically induced, Colitis/drug therapy, Colon/drug effects, Colon/pathology, Dextran Sulfate/pharmacology, Drug Interactions, Female, Interferon-gamma/metabolism, Interleukin-1, Interleukin-18/metabolism, Isoquinolines/pharmacology, Isoquinolines/therapeutic use, Lymph Nodes/drug effects, Lymph Nodes/metabolism, Lymphocyte Activation/drug effects, Mice, Mice, Inbred BALB C, Para-Aortic Bodies, Pyridazines/pharmacology, Pyridazines/therapeutic use, Spleen/pathology, T-Lymphocytes, Helper-Inducer/drug effects
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