The interleukin-1 beta-converting enzyme inhibitor pralnacasan reduces dextran sulfate sodium-induced murine colitis and T helper 1 T-cell activation.

Details

Serval ID
serval:BIB_CB8CB8D46DB2
Type
Article: article from journal or magazin.
Collection
Publications
Title
The interleukin-1 beta-converting enzyme inhibitor pralnacasan reduces dextran sulfate sodium-induced murine colitis and T helper 1 T-cell activation.
Journal
Journal of Pharmacology and Experimental Therapeutics
Author(s)
Loher F., Bauer C., Landauer N., Schmall K., Siegmund B., Lehr H.A., Dauer M., Schoenharting M., Endres S., Eigler A.
ISSN
0022-3565 (Print)
ISSN-L
0022-3565
Publication state
Published
Issued date
2004
Volume
308
Number
2
Pages
583-590
Language
english
Abstract
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.
Keywords
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
Pubmed
Create date
28/11/2011 18:53
Last modification date
20/08/2019 15:46
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