Journal
INFLAMMOPHARMACOLOGY
Volume 22, Issue 6, Pages 341-349Publisher
SPRINGER BASEL AG
DOI: 10.1007/s10787-014-0203-2
Keywords
Triterpenoid; Interleukin-17; Splenocytes; Colitis; Mice
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Funding
- Questcor Pharmaceuticals, Inc.
- Ellicott City [MD 21043]
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Introduction Synthetic triterpenoids inhibit IL-17 and improve autoimmune disease in mice. A prototype triter-penoid, 1-[2-cyano-3-, 12-dioxooleana-1,9(11)-dien-28oyl] imidazole (CDDO-Im), also inhibits signal transducer and activator of transcription 3 (STAT3) activation. Aims The goals of our study were twofold: (1) To determine if ex vivo treatment with CDDO-Im attenuated colonic IL-17 secretion from isolated splenocytes and colonic strips; (2) To determine if oral treatment with CDDO-Im improved DSS-induced colitis in mice. Methods Splenocytes were isolated from male Balb/c mice. Colitis was induced in rodents, with either trinitrobenzene sulfonic acid or dextran sulfate sodium (DSS). Colonic strips were collected 5 or 6 days after colitis induction. Splenocytes or colonic strips were exposed to CDDO-Im (0.5-2 mu M) concomitantly with IL-23 + IL-1 mu. Supernatants were collected after 48 or 24 h, and IL-17 was measured by ELISA. Using a DSS colitis model, mice were dosed orally with vehicle or CDDO-Im (20 mg/kg) over a 5-day period. Subsequently, various parameters of colitis were determined on study day 6. Results Ex vivo treatment with CDDO-Im inhibited IL-17 secretion from splenocytes and colonic strips. The IC50 values were <= 0.62 mu M. In vivo, CDDO-Im improved the altered colonic histology, and cytokine (IL-6, and IL-17) contents. Colonic STAT3 activation was also significantly reduced by CDDO-Im treatment. Summary CDDO-Im attenuated IL-17 secretion in ex vivo models of inflammation. In vivo, histological and biochemical parameters of colitis were improved in CDDO-Im treated mice. Conclusion CDDO-Im has a unique pharmacological profile, which supports further testing in animal models of IBD.
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