Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity
Natural killer (NK) cells are a potent weapon against tumor and viral infection. Finding active compounds with the capacity of enhancing NK cell effector functions will be effective to develop new anti-cancer drugs. In this study, we initially screened 287 commercially available active compounds by...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.680611/full |
| _version_ | 1818402297721389056 |
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| author | Baige Yao Baige Yao Qinglan Yang Qinglan Yang Yao Yang Yana Li Yana Li Hongyan Peng Hongyan Peng Shuting Wu Shuting Wu Lili Wang Lili Wang Shuju Zhang Shuju Zhang Minghui Huang Minghui Huang Erqiang Wang Erqiang Wang Peiwen Xiong Peiwen Xiong Ting Luo Ting Luo Liping Li Liping Li Sujie Jia Yafei Deng Yafei Deng Youcai Deng |
| author_facet | Baige Yao Baige Yao Qinglan Yang Qinglan Yang Yao Yang Yana Li Yana Li Hongyan Peng Hongyan Peng Shuting Wu Shuting Wu Lili Wang Lili Wang Shuju Zhang Shuju Zhang Minghui Huang Minghui Huang Erqiang Wang Erqiang Wang Peiwen Xiong Peiwen Xiong Ting Luo Ting Luo Liping Li Liping Li Sujie Jia Yafei Deng Yafei Deng Youcai Deng |
| author_sort | Baige Yao |
| collection | DOAJ |
| description | Natural killer (NK) cells are a potent weapon against tumor and viral infection. Finding active compounds with the capacity of enhancing NK cell effector functions will be effective to develop new anti-cancer drugs. In this study, we initially screened 287 commercially available active compounds by co-culturing with peripheral blood mononuclear cells (PBMCs). We found that five compounds, namely, Daphnetin, MK-8617, LW6, JIB-04, and IOX1, increased the IFN-γ+ NK cell ratio in the presence of IL-12. Further studies using purified human primary NK cells revealed that Daphnetin directly promoted NK cell IFN-γ production in the presence of IL-12 but not IL-15, while the other four compounds acted on NK cells indirectly. Daphnetin also improved the direct cytotoxicity of NK cells against tumor cells in the presence of IL-12. Through RNA-sequencing, we found that PI3K-Akt-mTOR signaling acted as a central pathway in Daphnetin-mediated NK cell activation in the presence of IL-12. This was further confirmed by the finding that both inhibitors of PI3K-Akt and its main downstream signaling mTOR, LY294002, and rapamycin, respectively, can reverse the increase of IFN-γ production and cytotoxicity in NK cells promoted by Daphnetin. Collectively, we identify a natural product, Daphnetin, with the capacity of promoting human NK cell activation via PI3K-Akt-mTOR signaling in the presence of IL-12. Our current study opens up a new potential application for Daphnetin as a complementary immunomodulator for cancer treatments. |
| first_indexed | 2024-12-14T08:06:08Z |
| format | Article |
| id | doaj.art-78e021f2dccd4138b97ecbaad8eb524a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T08:06:08Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-78e021f2dccd4138b97ecbaad8eb524a2022-12-21T23:10:11ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-12-011210.3389/fimmu.2021.680611680611Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct CytotoxicityBaige Yao0Baige Yao1Qinglan Yang2Qinglan Yang3Yao Yang4Yana Li5Yana Li6Hongyan Peng7Hongyan Peng8Shuting Wu9Shuting Wu10Lili Wang11Lili Wang12Shuju Zhang13Shuju Zhang14Minghui Huang15Minghui Huang16Erqiang Wang17Erqiang Wang18Peiwen Xiong19Peiwen Xiong20Ting Luo21Ting Luo22Liping Li23Liping Li24Sujie Jia25Yafei Deng26Yafei Deng27Youcai Deng28Hunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaDepartment of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaInstitute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaDepartment of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, ChinaHunan Children’s Research Institute (HCRI), Hunan Children’s Hospital, Changsha, ChinaHunan Provincial Key Laboratory of Children’s Emergency Medicine, Hunan Children’s Hospital, Changsha, ChinaInstitute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, ChinaNatural killer (NK) cells are a potent weapon against tumor and viral infection. Finding active compounds with the capacity of enhancing NK cell effector functions will be effective to develop new anti-cancer drugs. In this study, we initially screened 287 commercially available active compounds by co-culturing with peripheral blood mononuclear cells (PBMCs). We found that five compounds, namely, Daphnetin, MK-8617, LW6, JIB-04, and IOX1, increased the IFN-γ+ NK cell ratio in the presence of IL-12. Further studies using purified human primary NK cells revealed that Daphnetin directly promoted NK cell IFN-γ production in the presence of IL-12 but not IL-15, while the other four compounds acted on NK cells indirectly. Daphnetin also improved the direct cytotoxicity of NK cells against tumor cells in the presence of IL-12. Through RNA-sequencing, we found that PI3K-Akt-mTOR signaling acted as a central pathway in Daphnetin-mediated NK cell activation in the presence of IL-12. This was further confirmed by the finding that both inhibitors of PI3K-Akt and its main downstream signaling mTOR, LY294002, and rapamycin, respectively, can reverse the increase of IFN-γ production and cytotoxicity in NK cells promoted by Daphnetin. Collectively, we identify a natural product, Daphnetin, with the capacity of promoting human NK cell activation via PI3K-Akt-mTOR signaling in the presence of IL-12. Our current study opens up a new potential application for Daphnetin as a complementary immunomodulator for cancer treatments.https://www.frontiersin.org/articles/10.3389/fimmu.2021.680611/fullnatural killer cellDaphnetininterferon (IFN)-γPI3K-AktmTOR |
| spellingShingle | Baige Yao Baige Yao Qinglan Yang Qinglan Yang Yao Yang Yana Li Yana Li Hongyan Peng Hongyan Peng Shuting Wu Shuting Wu Lili Wang Lili Wang Shuju Zhang Shuju Zhang Minghui Huang Minghui Huang Erqiang Wang Erqiang Wang Peiwen Xiong Peiwen Xiong Ting Luo Ting Luo Liping Li Liping Li Sujie Jia Yafei Deng Yafei Deng Youcai Deng Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity Frontiers in Immunology natural killer cell Daphnetin interferon (IFN)-γ PI3K-Akt mTOR |
| title | Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity |
| title_full | Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity |
| title_fullStr | Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity |
| title_full_unstemmed | Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity |
| title_short | Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity |
| title_sort | screening for active compounds targeting human natural killer cell activation identifying daphnetin as an enhancer for ifn γ production and direct cytotoxicity |
| topic | natural killer cell Daphnetin interferon (IFN)-γ PI3K-Akt mTOR |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.680611/full |
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