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


OBJECTIVE
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.


CONCLUSIONS
CDDO-Im has a unique pharmacological profile, which supports further testing in animal models of IBD.
Department of Pharmaceutical and Biomedical Sciences, California Northstate University College of Pharmacy, Rancho Cordova, CA, 95670, USA, lfitzpatrick@cnsu.edu.
Leo R
LR
Fitzpatrick
Elizabeth
E
Stonesifer
Jeffrey S
JS
Small
Karen T
KT
Liby
D000818:Animals; D003092:Colitis / Q000188:drug therapy* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D020128:Inhibitory Concentration 50; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D007093:Imidazoles; D020381:Interleukin-17; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009828:Oleanolic Acid; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate