Journal
FRONTIERS IN IMMUNOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2018.01509
Keywords
natural killer cells; natural products; interferon gamma; diphyllin; immunotherapy
Categories
Funding
- US National Institutes of Health [CA185301, AI129582, NS106170]
- American Cancer Society Research Scholar Grant [RSG-14-243-01-LIB]
- Leukemia & Lymphoma Society
- Gabrielle's Angel Foundation for Cancer Research
- National Natural Science Foundation of China [21372132, 31571991, 81673155]
- National Key Research & Development Program of China [2017YFD0200900]
- Fundamental Research Funds for the Central Universities [020/63171311]
- International Science & Technology Cooperation Program of China [2014DFR41030]
- China Agricultural University (the Key Technologies R&D Program of China) [2015BAK45B01]
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Natural products and their derivatives have long been used as pharmacological agents in the fight against cancer. Human natural killer (NK) cells are critical in our immune system in that they are capable of destroying tumor cells directly. However, there are few reports that elucidate the role of natural products in activating NK cells. In this study, we discovered that a synthetic disaccharide derivative of diphyllin, 4-O-{[2 '',3 '',4 ''-tri-O-acetyl-alpha-D-arabinopyranosyl-(1 ''-> 4 ')]-2 ',3 '-di-O-acetyl-alpha-L-rhamnopyranosyl}diphyllin (TAARD), can alone stimulate interferon (IFN)-gamma secretion in primary human NK cells and the NKL cell line. Additionally, it had an additive effect with IL-12 or IL-15 on IFN-gamma production, but little adverse effects on NK cells. Mechanistically, TAARD induced the phosphorylation of NF-kappa B and STAT3, resulting in their binding on the IFNG promoter, which was dependent on TLR1 and TLR3 signaling, respectively. STAT3 and NF-kappa B knockdown with lentivirus shRNA as well as the NF-kappa B-specific inhibitor, N-tosyl-L-phenylalaninechloromethyl ketone, significantly suppressed TAARD-induced IFN-gamma generation in primary NK cells. Blockade of TLR1 and TLR3 with neutralizing antibodies considerably decreased TAARD-induced activation of NF-kappa B and STAT3, respectively, as well as IFN-gamma generation in NK cells. Collectively, our data suggest that TAARD can induce NK cell IFN-gamma production through TLR1-NF-kappa B and TLR3-STAT3 signaling pathways, rendering its potential use as an agent for cancer prevention or treatment.
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