Exploration of a novel immunomodulatory compound: Molecular mechanism of action and clinical application

During screening of anti-cancer drugs, it was found that one Amaryllidaceae alkaloid designated sodium narcistatin (SNS) exhibited potent immunomodulatory activity. In vitro experiments in a macrophage cell line showed that SNS had a very similar mode of action with a well-described protein synthesis inhibitor and a ribotoxin anisomycin. SNS activated p38 MAPK pathway leading to upregulation of production of cyclooxygenase-2. However, protein synthesis of other lipopolysaccharide (LPS)-induced pro-inflammatory factors, such as inducible nitric oxide synthase, and production of nitric oxide, monocytic chemoattractant protein-1, and pro-matrix metalloproteinase-9 was significantly decreased after treatment with SNS at subinhibitory doses. In vivo experiments of systemic treatment with SNS in wild type and immunocompromiced mice revealed that SNS selectively inhibited differentiation of dendritic cells (DCs), reducing expression of DC-specific phenotypical and activation markers. However, SNS significantly facilitated differentiation of bone marrow cells into granulocytes. In addition, migration of neutrophils and production of chemokines and cytokines was significantly increased in air pouch model synergizing the effect of LPS.; In conclusion, SNS exerted a dual immunomodulatory effect. When applied systemically, anti-inflammatory qualities of this drug, such as inhibition of synthesis of pro-inflammatory factors and differentiation of DCs were utilized in treatment of murine arthritis. However, local treatment with SNS in conjunction with LPS showed significant reduction in murine tumor growth.