Identification of an IKKβ inhibitor for inhibition of inflammation in vivo and in vitro

Publication date: Available online 31 August 2019Source: Pharmacological ResearchAuthor(s): Qi Chen, Juan Liu, Yuxin Zhuang, Li-ping Bai, Qing Yuan, Silin Zheng, Kangsheng Liao, Md. Asaduzzaman Khan, Qibiao Wu, Cheng Luo, Liu Liang, Hui Wang, Ting LiAbstractTargeting on the IKKβ to discover anti-inflammatory drugs has been launched for ten years, due to its predominant role in canonical NF-κB signaling. In the current study, we identified a novel IKKβ inhibitor, ellipticine (ELL), an alkaloid isolated from Ochrosia elliptica and Rauvolfia sandwicensis. We found that ELL reduced the secretion and mRNA expression of TNF-α and IL-6 and decreased the protein expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in bone marrow derived macrophages (BMDMs) stimulated with LPS. In coincided with the results, ELL suppressed PGE2 and NO production in BMDMs. Underlying mechanistic study showed that ELL inhibited IκBα phosphorylation and degradation as well as NF-κB nuclear translocation, which was attributed to suppression of IKKα/β activation. Furthermore, kinase assay and binding assay results indicated that ELL inhibited IKKβ activity via directly binding to IKKβ and in turn resulted in suppression of NF-κB signaling. To identify the binding sites of ELL on IKKβ, IKKβC46A plasmid was prepared and the kinase assay was performed. The results demonstrated that the inhibitory effect of ELL on IKKβ activity was impaired in the mutation, implying ...
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research