期刊
INFLAMMOPHARMACOLOGY
卷 28, 期 2, 页码 499-511出版社
SPRINGER BASEL AG
DOI: 10.1007/s10787-019-00643-z
关键词
VPR-254; Ror gamma t; Colitis; Mice; Inflammatory bowel disease
资金
- NIDDK NIH HHS [1R43 DK099896, 2R44 DK098896, 2R44 DK098896, 1R43 DK099896] Funding Source: Medline
Introduction Retinoic Acid Related Orphan Nuclear Receptor gamma T (ROR gamma T) is a lineage specifying transcription factor for IL-17 expressing cells, which may contribute to the pathogenesis of Inflammatory Bowel Disease (IBD). VPR-254 is a selective in vitro inhibitor of ROR gamma T. Aims The main goals of our study were twofold: (1) To determine if ex vivo treatment with VPR-254 reduced relevant cytokine (IL-17 and IL-21) secretion from colonic strips of mice with colitis; (2) To determine if treatment of mice with VPR-254 attenuated parameters of colitis, using three murine IBD models. Methods VPR-254 was evaluated ex vivo in a colonic strip assay, using tissue from mice with Dextran sulfate sodium (DSS)-induced colitis. In vivo, VPR-254 was evaluated for efficacy in DSS, Trintirobenzenesulfonic acid (TNBS) and Anti-CD40 antibody-induced murine models of colitis. Results VPR-254 reduced the production of key pro-inflammatory cytokines (e.g., IL-17) in ex vivo and in vivo models of colitis. This small molecule inhibitor of ROR gamma T also improved various morphometric and histological parameters associated with three diverse murine models of IBD. Conclusion Our results support the concept that an inhibitor of ROR-gamma T may have potential utility for the treatment of IBD.
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