The interleukin-1 beta-converting enzyme inhibitor pralnacasan reduces dextran sulfate sodium-induced murine colitis and T helper 1 T-cell activation.
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.
Loher
Florian
F
Division of Clinical Pharmacology, Medizinische Klinik Innenstadt of the University of Munich, Germany.
Bauer
Christian
C
Landauer
Nikola
N
Schmall
Kathrin
K
Siegmund
Britta
B
Lehr
Hans Anton
HA
Dauer
Marc
M
Schoenharting
Martin
M
Endres
Stefan
S
Eigler
Andreas
A
D000818:Animals; D001381:Azepines / Q000494:pharmacology* / Q000627:therapeutic use; D061945:Caspase Inhibitors; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D003106:Colon / Q000187:drug effects / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1; D020382:Interleukin-18 / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010220:Para-Aortic Bodies; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D013154:Spleen / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects*
D001381:Azepines; D061945:Caspase Inhibitors; D007375:Interleukin-1; D020382:Interleukin-18; D007546:Isoquinolines; D011724:Pyridazines; D007371:Interferon-gamma; D016264:Dextran Sulfate; C476331:pralnacasan