Dehydrocostus Lactone Suppresses Dextran Sulfate Sodium-Induced Colitis by Targeting the IKKα/β-NF-κB and Keap1-Nrf2 Signalling Pathways

• Published in: Frontiers in pharmacology 2022-03, Vol.13, p.817596-817596
• Main Authors: Yuan, Yun, Hu, Qiongying, Liu, Lu, Xie, Fan, Yang, Luyao, Li, Yuchen, Zhang, Chuantao, Chen, Hongqing, Tang, Jianyuan, Shen, Xiaofei
• Format: Article
• Language: English
• Subjects: colitis; dehydrocostus lactone; IKKα/β-NF-κB pathway; inflammation; Keap1-Nrf2 pathway; macrophages; Pharmacology
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2022.817596

Dehydrocostus lactone (DCL) is a major sesquiterpene lactone isolated from , a traditional Chinese herbal medicine that used to treat gastrointestinal diseases. This study aimed to examine the therapeutic effects of DCL on dextran sulfate sodium (DSS)-induced colitis with a focus on identifying the molecular mechanisms involved in DCL-mediated anti-inflammatory activity in macrophages. First, oral administration of DCL (5-15 mg/kg) not only ameliorated symptoms of colitis and colonic barrier injury, but also inhibited the expression of proinflammatory cytokines and myeloperoxidase in colon tissues in DSS-challenged mice. Furthermore, DCL also exhibited significant anti-inflammatory activity in LPS/IFNγ-stimulated RAW264.7 macrophages. Importantly, DCL significantly suppressed the phosphorylation and degradation of IκBα and subsequent NF-κB nuclear translocation, and enhanced the nuclear accumulation of Nrf2 in LPS/IFNγ-treated RAW264.7 cells. Mechanistically, DCL could directly interact with IKKα/β and Keap1, thereby leading to the inhibition of NF-κB signalling and the activation of Nrf2 pathway. Furthermore, DCL-mediated actions were abolished by dithiothreitol, suggesting a thiol-mediated covalent linkage between DCL and IKKα/β or Keap1. These findings demonstrated that DCL ameliorates colitis by targeting NF-κB and Nrf2 signalling, suggesting that DCL may be a promising candidate in the clinical treatment of colitis.