Vidofludimus inhibits colonic interleukin-17 and improves hapten-induced colitis in rats by a unique dual mode of action.
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.
Department of Pharmacology, Penn State College of Medicine, Hummelstown, PA 17036, USA. lfitzpatrick@psu.edu
Leo R
LR
Fitzpatrick
Jeffrey S
JS
Small
Robert
R
Doblhofer
Aldo
A
Ammendola
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D005260:Female; D006241:Haptens / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology*; D014529:Uridine / Q000494:pharmacology
D001713:Biphenyl Compounds; D017252:CD3 Complex; D003998:Dicarboxylic Acids; D006241:Haptens; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014302:Trinitrobenzenesulfonic Acid; C553728:vidofludimus; D014529:Uridine