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Vidofludimus Inhibits Colonic Interleukin-17 and Improves Hapten-Induced Colitis in Rats by a Unique Dual Mode of Action
- Source :
- Journal of Pharmacology and Experimental Therapeutics. 342:850-860
- Publication Year :
- 2012
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2012.
-
Abstract
- Vidofludimus (Vido) is a novel oral immunomodulatory drug that inhibits dihydro-orotate dehydrogenase and lymphocyte proliferation in vitro. Vido inhibits interleukin (IL)-17 secretion in vitro independently of effects on lymphocyte proliferation. Our primary goal was to evaluate the in vivo effects of Vido on IL-17 secretion and the parameters of trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. To further delineate the mechanism of action for Vido, rats were dosed concomitantly with uridine (Uri). Young Wistar rats received a 150-μl enema of either phosphate-buffered saline (PBS) or TNBS on study day 1. The ex vivo effects of Vido on 24-h colonic IL-17 secretion were determined by using colonic strips from PBS- or TNBS-treated rats. Some rats were dosed with vehicle, Vido, or Vido + Uri for 6 days. On day 6, the parameters of colitis were determined from colonic tissue. These parameters included macroscopic, histological, and transcription factor measurements, IL-17 production, and numbers of CD3+ T cells. Ex vivo Vido completely blocked IL-23 + IL-1β-stimulated secretion of IL-17 by colonic strips. In vivo Vido treatment alone most effectively reduced macroscopic and histological pathology and the numbers of CD3+ T cells. In contrast, similarly reduced nuclear signal transducer and activator of transcription 3 (STAT3) binding and IL-17 levels were observed from animals treated with Vido alone and Vido + Uri. Vido improves TNBS-induced colonic inflammation by a unique dual mode of action: 1) inhibiting expansion of colonic T lymphocytes, and 2) suppressing colonic IL-17 production, which is independent from the control of T-lymphocyte proliferation, by inhibition of STAT3 and nuclear factor-κB activation.
- Subjects :
- STAT3 Transcription Factor
CD3 Complex
Colon
T-Lymphocytes
Interleukin-1beta
Lymphocyte proliferation
Pharmacology
Interleukin-23
In vivo
medicine
Animals
Dicarboxylic Acids
Rats, Wistar
Colitis
Uridine
Cell Proliferation
Inflammation
business.industry
Biphenyl Compounds
Interleukin-17
NF-kappa B
Interleukin
medicine.disease
digestive system diseases
Rats
Biphenyl compound
Trinitrobenzenesulfonic Acid
Mechanism of action
Immunology
Molecular Medicine
Female
Interleukin 17
medicine.symptom
business
Haptens
Ex vivo
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 342
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....9ad7574951dfef4d6f8b3f30856dcebd