The Natural Product Phyllanthusmin C Enhances IFN-γ Production by Human NK Cells through Upregulation of TLR-Mediated NF-κB Signaling

Natural products are a major source for cancer drug development. NK cells are a critical component of innate immunity with the capacity to destroy cancer cells, cancer-initiating cells, and clear viral infections. However, few reports describe a natural product that stimulates NK cell IFN-gamma production and unravel a mechanism of action. In this study, through screening, we found that a natural product, phyllanthusmin C (PL-C), alone enhanced IFN-gamma production by human NK cells. PL-C also synergized with IL-12, even at the low cytokine concentration of 0.1 ng/ml, and stimulated IFN-gamma production in both human CD56(bright) and CD56(dim) NK cell subsets. Mechanistically, TLR1 and/or TLR6 mediated PL-C's activation of the NF-kappa B p65 subunit that in turn bound to the proximal promoter of IFNG and subsequently resulted in increased IFN-gamma production in NK cells. However, IL-12 and IL-15Rs and their related STAT signaling pathways were not responsible for the enhanced IFN-gamma secretion by PL-C. PL-C induced little or no T cell IFN-gamma production or NK cell cytotoxicity. Collectively, we identify a natural product with the capacity to selectively enhance human NK cell IFN-gamma production. Given the role of IFN-gamma in immune surveillance, additional studies to understand the role of this natural product in prevention of cancer or infection in select populations are warranted.