Der Interleukin-1β-converting-enzyme-Inhibitor Pralnacasan reduziert die Dextran-Sulfat-Sodium-induzierte Kolitis und die IL-18-vermittelte Th1-Zell-Aktivierung
Beschreibung
vor 18 Jahren
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.
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.
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