VPR-254: an inhibitor of ROR-gamma T with potential utility for the treatment of inflammatory bowel disease.
Adult
Animals
CHO Cells
Cricetulus
Cytokines
/ metabolism
Dextran Sulfate
Disease Models, Animal
Female
Humans
Inflammatory Bowel Diseases
/ drug therapy
Interleukin-17
/ metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, SCID
Nuclear Receptor Subfamily 1, Group F, Member 3
/ antagonists & inhibitors
Colitis
Inflammatory bowel disease
Mice
Rorγt
VPR-254
Journal
Inflammopharmacology
ISSN: 1568-5608
Titre abrégé: Inflammopharmacology
Pays: Switzerland
ID NLM: 9112626
Informations de publication
Date de publication:
Apr 2020
Apr 2020
Historique:
received:
23
05
2019
accepted:
09
09
2019
pubmed:
25
9
2019
medline:
5
1
2021
entrez:
25
9
2019
Statut:
ppublish
Résumé
Retinoic Acid Related Orphan Nuclear Receptor gamma T (RORγT) 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 RORγT. 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. 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. 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 RORγT also improved various morphometric and histological parameters associated with three diverse murine models of IBD. Our results support the concept that an inhibitor of ROR-gamma T may have potential utility for the treatment of IBD.
Identifiants
pubmed: 31549280
doi: 10.1007/s10787-019-00643-z
pii: 10.1007/s10787-019-00643-z
doi:
Substances chimiques
Cytokines
0
Interleukin-17
0
Nuclear Receptor Subfamily 1, Group F, Member 3
0
Dextran Sulfate
9042-14-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
499-511Subventions
Organisme : NIDDK NIH HHS
ID : 1R43 DK099896
Pays : United States
Organisme : NIDDK NIH HHS
ID : 2R44 DK098896
Pays : United States
Organisme : NIDDK NIH HHS
ID : 1R43 DK099896
Pays : United States
Organisme : NIDDK NIH HHS
ID : 2R44 DK098896
Pays : United States
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