Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity.
Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity.
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筛选针对人类自然杀伤细胞激活的活性化合物 鉴定瑞香素作为 IFN-γ 产生和直接细胞毒性的增强剂
DOI：
10.3389/fimmu.2021.680611
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发表时间：
2021
影响因子：
7.3
通讯作者：
Deng Y
中科院分区：
文献类型：
--
作者：
Yao B;Yang Q;Yang Y;Li Y;Peng H;Wu S;Wang L;Zhang S;Huang M;Wang E;Xiong P;Luo T;Li L;Jia S;Deng Y;Deng Y
自然杀伤（NK）细胞是对抗肿瘤和病毒感染的有力武器。寻找具有增强NK细胞效应功能的活性化合物将有助于开发新的抗肿瘤药物。在这项研究中，我们初步筛选了287个市售的活性化合物与外周血单核细胞（PBMC）的共培养。我们发现五种化合物，即瑞香素、MK-8617、LW 6、JIB-04和IOX 1，在IL-12存在下增加IFN-γ+ NK细胞比率。进一步研究表明，瑞香素在IL-12的作用下能直接促进NK细胞IFN-γ的产生，而在IL-15的作用下不能，而其它4种化合物则是间接作用于NK细胞。瑞香素还提高了在IL-12存在下NK细胞对肿瘤细胞的直接细胞毒性。通过RNA测序，我们发现PI 3 K-Akt-mTOR信号传导在IL-12存在下在瑞香素介导的NK细胞活化中充当中心途径。这进一步通过以下发现证实：PI 3 K-Akt及其主要下游信号传导mTOR的抑制剂LY 294002和雷帕霉素分别可以逆转瑞香素促进的NK细胞中IFN-γ产生和细胞毒性的增加。总的来说，我们鉴定了一种天然产物瑞香素，其具有在IL-12存在下通过PI 3 K-Akt-mTOR信号传导促进人NK细胞活化的能力。我们目前的研究为瑞香素作为癌症治疗的补充免疫调节剂开辟了一个新的潜在应用。
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.
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