A novel fluorinated triazole derivative suppresses macrophage activation and alleviates experimental colitis via a Twist1-dependent pathway.

Abstract

Hyperactivated macrophages play a key role in the initiation and perpetuation of mucosal inflammation in Crohn's disease (CD). Increasing evidence suggests that the basic helix-loop-helix (bHLH) repressor Twist1 can suppress activation of nuclear factor-κB (NF-κB) and the subsequent production of TNF-α, which are both essential elements of macrophage activation. Thus, developing novel therapeutic strategies to enhance Twist1 expression and to inhibit macrophage activation may be beneficial for CD treatment. In the present study, a series of trifluoroethyl thiazolo[3,2-b][1,2,4]triazole derivatives were used to investigate their potential anti-inflammatory activities and the underlying mechanism. In a biological activity screen, compound 7# (Thiazolo[3,2-b][1,2,4]triazole-5-methanamine, 6-phenyl-α-(trifluoromethyl)-, (αR)-, TT-TFM) suppressed the activation of macrophages. Consistent with the in vitro data, TT-TFM protected against 2,4,6-trinitrobenzene sulfonic acid (TNBS), dextran sulfate sodium (DSS)-induced acute colitis and IL-10 knockout (KO) chronic colitis, as judged by body weight changes and colonic pathological damage. A mechanistic study based on microarray analysis and gene interference experiments indicated that TT-TFM exerted anti-inflammatory effects by enhancing Twist1 expression and subsequently blocking the NF-κB/TNF-α pathway. In addition, pretreatment with lentiviruses encoding shRNA targeting Twist1 could abolish the therapeutic effect of TT-TFM in TNBS colitis. Ultimately, TT-TFM showed anti-colitis activity by reducing NF-κB activation and the TNF-α level by promoting Twist1 expression; thus, TT-TFM may offer a therapeutic strategy for CD patients.

• Authors: Tingyue Tu, Mao Yu, Yanping Zhang, Xiafei Shi, Jinhao Xu, Junqing Hu, Jingjing Gan, Wei He, Lei Dong, Jianlin Han, Zhen Huang, Yi Pan, Junfeng Zhang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 155 Pg. 275-287 (09 2018) ISSN: 1873-2968 [Electronic] England
• PMID: 30028990 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Nuclear Proteins
• Triazoles
• Twist-Related Protein 1
• Twist1 protein, mouse
• Trifluoroethanol

Topics

• Animals
• Cells, Cultured
• Colitis (drug therapy, metabolism)
• Female
• Macrophage Activation (drug effects, physiology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Mice, Knockout
• Nuclear Proteins (agonists, biosynthesis)
• Signal Transduction (drug effects, physiology)
• Triazoles (chemistry, pharmacology, therapeutic use)
• Trifluoroethanol (chemistry, pharmacology, therapeutic use)
• Twist-Related Protein 1 (agonists, biosynthesis)