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.
Footnotes
This work was supported by funding from 4SC AG, Planegg-Martinsried, Germany.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- IBD
- inflammatory bowel disease
- CD
- Crohn's disease
- IL
- interleukin
- TNBS
- trinitrobenzene sulfonic acid
- PBS
- phosphate-buffered saline
- Vido
- vidofludimus
- Uri
- uridine
- STAT
- signal transducer and activator of transcription
- DHODH
- dihydro-orotate dehydrogenase
- PCNA
- proliferating cell nuclear antigen
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick end labeling
- PBMC
- peripheral blood mononuclear cell
- NF-κB
- nuclear factor-κB
- MPO
- myeloperoxidase
- 4SC-101
- 2-(3-Fluoro-3'-methoxybiphenyl-4-ylcarbamoyl)-cyclopent-1-enecarboxylic acid.
- Received January 19, 2012.
- Accepted June 11, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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