title: The natural product phyllanthusmin C enhances IFN-γ production by human NK cells through upregulation of TLR-mediated NF-κB signaling.
abstract: 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-γ 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-γ 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-γ 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-κB p65 subunit that in turn bound to the proximal promoter of IFNG and subsequently resulted in increased IFN-γ production in NK cells. However, IL-12 and IL-15Rs and their related STAT signaling pathways were not responsible for the enhanced IFN-γ secretion by PL-C. PL-C induced little or no T cell IFN-γ production or NK cell cytotoxicity. Collectively, we identify a natural product with the capacity to selectively enhance human NK cell IFN-γ production. Given the role of IFN-γ in immune surveillance, additional studies to understand the role of this natural product in prevention of cancer or infection in select populations are warranted.
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210; Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China;
authors.forename: Youcai
authors.initials: Y
authors.lastname: Deng
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Jianhong
authors.initials: J
authors.lastname: Chu
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210;
authors.forename: Yulin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China;
authors.forename: Zhijin
authors.initials: Z
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China;
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Ji
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Bethany
authors.initials: B
authors.lastname: Mundy-Bosse
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; Department of Lymphoma, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China;
authors.forename: Shunzong
authors.initials: S
authors.lastname: Yuan
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hughes
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH 43210;
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210;
authors.forename: Baljash
authors.initials: B
authors.lastname: Cheema
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Camardo
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH 43210;
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH 43210;
authors.forename: Lai-Chu
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226; and.
authors.forename: Li-Shu
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: He
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210;
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Kinghorn
authors.affiliation: Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; jianhua.yu@osumc.edu michael.caligiuri@osumc.edu lpsh008@aliyun.com.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; jianhua.yu@osumc.edu michael.caligiuri@osumc.edu lpsh008@aliyun.com.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; jianhua.yu@osumc.edu michael.caligiuri@osumc.edu lpsh008@aliyun.com.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
mesh_terms: D052117:Benzodioxoles / Q000494:pharmacology*; D019002:CD56 Antigen / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D006027:Glycosides / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D053647:Receptors, Interleukin-15; D015398:Signal Transduction / Q000276:immunology; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000276:immunology; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D052117:Benzodioxoles; D019002:CD56 Antigen; D006027:Glycosides; C569274:IL15 protein, human; D019409:Interleukin-15; C522918:NCAM1 protein, human; D034741:RNA, Small Interfering; D053647:Receptors, Interleukin-15; C495368:TLR6 protein, human; D051194:Toll-Like Receptor 1; D051216:Toll-Like Receptor 6; D051996:Transcription Factor RelA; C514009:phyllanthusmin C; D018664:Interleukin-12; D007371:Interferon-gamma