Abstract
Vidofludimus (Vido) is a novel oral immunomodulatory drug that inhibits dihydroorotate dehydrogenase and lymphocyte proliferation in vitro. Vido inhibits IL-17 secretion in vitro independently of effects on lymphocyte proliferation. Aim: Our primary goal was to evaluate the in vivo effects of Vido on IL-17 secretion and parameters of TNBS-induced colitis in rats. Secondarily, to further delineate the mechanism of action for Vido, rats were dosed concomitantly with Uridine (Uri). Methods: Young Wistar rats received a 150 µL enema of either PBS or TNBS on study day 1. The ex vivo effects of Vido on 24-hour colonic IL-17 secretion were determined using colonic strips from PBS or TNBS treated rats. Some rats were dosed with vehicle, Vido or Vido + Uri for a six-day period. On day 6, 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. Results: 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 numbers of CD3+ T cells. In contrast, similarly reduced nuclear STAT3 binding and IL-17 levels were observed from animals treated with Vido alone and Vido + Uri. Conclusions: 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 decoupled from the control of T-lymphocyte proliferation, by inhibition of STAT3 and NF-κB activation.
- Received January 19, 2012.
- Revision received May 2, 2012.
- Accepted June 11, 2012.
- The American Society for Pharmacology and Experimental Therapeutics