Nitidine chloride exerts anti-inflammatory action by targeting Topoisomerase I and enhancing IL-10 production

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.

Chelerythrine Chloride (PubChem CID: 72311); DNA topoisomerase I inhibitor; Endotoxemia; Interleukin-10; Irinotecan hydrochloride (PubChem CID: 74990); LY294002 (PubChem CID: 3973); Lipopolysaccharide; MK-2206 (PubChem CID: 46930998); Nitidine Chloride (PubChem CID: 25659); Phosphatidylinositol 3-kinase/Akt pathway; SN-38 (PubChem CID: 104842); Sanguinarine chloride (PubChem CID: 68635); Topotecan hydrochloride (PubChem CID: 60699).