Bauer, Christian (2006): Der Interleukin-1β-converting-enzyme-Inhibitor Pralnacasan reduziert die Dextran-Sulfat-Sodium-induzierte Kolitis und die IL-18-vermittelte Th1-Zell-Aktivierung. Dissertation, LMU München: Faculty of Medicine |
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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.
Item Type: | Theses (Dissertation, LMU Munich) |
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Keywords: | Morbus Crohn, Colitis ulcerosa, Pralnacasan, IL-18 |
Subjects: | 600 Technology, Medicine 600 Technology, Medicine > 610 Medical sciences and medicine |
Faculties: | Faculty of Medicine |
Language: | German |
Date of oral examination: | 4. May 2006 |
1. Referee: | Endres, Stefan |
MD5 Checksum of the PDF-file: | 55777f4c81e7a22d6892ec6432235b60 |
Signature of the printed copy: | 0700/UMD 11611 |
ID Code: | 5366 |
Deposited On: | 19. Jun 2006 |
Last Modified: | 24. Oct 2020 09:29 |