Epoxymicheliolide prevents dextran sulfate sodium-induced colitis in mice by inhibiting TAK1-NF-?B pathway and activating Keap1-NRF2 signaling in macrophages

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作   者：

He, Jinchen;  Liu, Lu;  Liu, Xiaojun;  Chen, Hongqing;  Liu, Keyun;  Huang, Ning;  Wang, Yi; 

作者机构：

Chengdu Univ Tradit Chinese Med;  Hubei Univ Nationalities;  Sichuan Univ; 

关键词：

TAK1;  Keap1-NRF2 signaling;  Epoxymicheliolide;  Anti-inflammatory effect;  Macrophages;  TAK1-NF;  ?B pathway;  NF-KAPPA-B;  Ulcerative colitis; 

期刊名称：

International immunopharmacology

i s s n：

1567-5769

年卷期：

2022 年 113PA 卷

页   码：

109404-109404

页   码：

摘   要：

Ulcerative colitis (UC) is an unspecific colorectal inflammation associated with macrophages overactivation. Therefore, macrophage-targeted treatment has been considered a promising strategy for UC therapy. Epoxymicheliolide (EMCL) is a compound from Aucklandia lappa Decne, a TCM for treating gastrointestinal inflammatory diseases. The purpose of this study is to investigate the therapeutic effect of EMCL on DSS-induced mice colitis through the anti-inflammatory activity on macrophages and its underlying mechanisms. We found that EMCL inhibited the release of NO and PGE2 by down-regulating the expression of iNOS and COX2, while suppressed the expression of IL-1 beta, IL-6, and TNF-alpha in LPS-stimulated RAW264.7 macrophages. EMCL also inhibited NO production in LPS-activated peritoneal macrophages and TNF alpha-stimulated RAW264.7 cells. Moreover, EMCL blocked the phosphorylation of TAK1, IKK alpha/beta, and I kappa B alpha, as well as I kappa B alpha degradation, thereby inhibiting the NF kappa B pro-inflammatory signaling. Furthermore, EMCL decreased the intracellular ROS, by activating the NRF2 antioxidant pathway. CETSA and molecular docking showed that EMCL might form a covalent bond with Cys174 of TAK1 or Cya151 of Keap1, which may contribute to EMCL-mediated actions. Additionally, a thiol donor beta-mercaptoethanol obviously abolished EMCL-mediated actions in vitro, suggesting the crucial role of the alpha, gamma-unsaturated lactone of EMCL on its anti-inflammatory effects. Furthermore, EMCL not only ameliorated symptoms of colitis and colon barrier injury, but also decreased the levels of pro-inflammatory cytokines, MPO, NO, and MDA in DSS-challenged mice. Thus, our study demonstrated that EMCL ameliorated UC by targeting NF kappa B and Nrf2 pathways, indicating it may server as a promising drug candidate for UC therapy.