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

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. 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.

• Authors: Leo R Fitzpatrick, Elizabeth Stonesifer, Jeffrey S Small, Karen T Liby
• Journal: Inflammopharmacology (Inflammopharmacology) Vol. 22 Issue 6 Pg. 341-9 (Dec 2014) ISSN: 1568-5608 [Electronic] Switzerland
• PMID: 24715223 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• Imidazoles
• Interleukin-17
• Interleukin-6
• STAT3 Transcription Factor
• STAT3 protein, human
• Oleanolic Acid
• Trinitrobenzenesulfonic Acid
• Dextran Sulfate

Topics

• Animals
• Colitis (drug therapy, pathology)
• Dextran Sulfate (toxicity)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme-Linked Immunosorbent Assay
• Imidazoles (administration & dosage, pharmacology)
• Inflammation (drug therapy, pathology)
• Inhibitory Concentration 50
• Interleukin-17 (antagonists & inhibitors, metabolism)
• Interleukin-6 (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Oleanolic Acid (administration & dosage, analogs & derivatives, pharmacology)
• STAT3 Transcription Factor (antagonists & inhibitors)
• Spleen (cytology, drug effects)
• Time Factors
• Trinitrobenzenesulfonic Acid