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01.12.2014 | Research Article | Ausgabe 6/2014

Inflammopharmacology 6/2014

The synthetic triterpenoid (CDDO-Im) inhibits STAT3, as well as IL-17, and improves DSS-induced colitis in mice

Zeitschrift:
Inflammopharmacology > Ausgabe 6/2014
Autoren:
Leo R. Fitzpatrick, Elizabeth Stonesifer, Jeffrey S. Small, Karen T. Liby

Abstract

Introduction

Synthetic triterpenoids inhibit IL-17 and improve autoimmune disease in mice. A prototype triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] 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 μM) concomitantly with IL-23 + IL-1β. 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 μM. 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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