Nitidine chloride exerts anti-inflammatory action by targeting Topoisomerase I and enhancing IL-10 production. (October 2019)

• Record Type: Journal Article
• Authors: Yang, Niao; Yue, Rongcai; Ma, Jinzhu; Li, Wencai; Zhao, Zeng; Li, Huiliang; Shen, Yunheng; Hu, Zhenlin; Lv, Chao; Xu, Xike; Yang, Yili; Dai, Xiankun; Liu, Xia; Yu, Yizhi; Zhang, Weidong
• Is Part Of: Pharmacological research. Volume 148(2019)
• Publication Date: 2019-10
• Subjects: BMDCs bone marrow-derived dendritic cells -- CC chelerythrine chloride -- CPT-11 irinotecan hydrochloride -- GSK3β glycogen synthase kinase 3β -- H-E hematoxylin and eosin -- LPS lipopolysaccharide -- NC nitidine chloride -- PI3K phosphoinositide 3-kinase -- PMs peritoneal macrophages -- SC sanguinarine chloride -- TLR Toll-like receptor -- TOP1 Topoisomerase 1 -- TPT topotecan hydrochloride; Nitidine Chloride (PubChem CID: 25659) -- Chelerythrine Chloride (PubChem CID: 72311) -- Sanguinarine chloride (PubChem CID: 68635) -- Topotecan hydrochloride (PubChem CID: 60699) -- Irinotecan hydrochloride (PubChem CID: 74990) -- SN-38 (PubChem CID: 104842) -- LY294002 (PubChem CID: 3973) -- MK-2206 (PubChem CID: 46930998); Interleukin-10 -- DNA topoisomerase I inhibitor -- Lipopolysaccharide -- Endotoxemia -- Phosphatidylinositol 3-kinase/Akt pathway; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.104368
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: In the effort to identify natural products that regulate immunity and inflammation, we found that nitidine chloride (NC), an alkaloid from herb Zanthoxylum nitidum, enhanced IL-10 production in lipopolysaccharide (LPS)-stimulated myeloid cells. While NC was shown to be capable of inhibiting topoisomerase I (TOP1), NC analogs that could not inhibit TOP1 failed to increase IL-10 production. Moreover, medicinal TOP1 inhibitors TPT and SN-38 also augmented IL-10 production significantly, whereas knockdown of TOP1 prevented NC, TPT, and SN-38 from enhancing IL-10 expression. Thus, NC promoted IL-10 production by inhibiting TOP1. In LPS-induced endotoxemic mice, NC and TOP1 inhibitors increased IL-10 production, suppressed inflammatory responses, and reduced mortality remarkably. The anti-inflammatory activities of TOP1 inhibition were markedly reduced by IL-10-neutralizing antibody and largely absent in IL-10-deficient mice. In LPS-stimulated RAW264.7 cells and in peritoneal macrophages from endotoxemic mice, NC and TOP1 inhibitors significantly enhanced the activation of Akt, a critical signal transducer for IL-10 production, and inhibition of Akt prevented these compounds from enhancing IL-10 production and ameliorating endotoxemia. These data indicated that NC and TOP1 inhibitors are able to exert anti-inflammatory action through enhancing Akt-mediated IL-10 production and may assist with the treatment of inflammatory diseases.