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Suppressor of cytokine signaling 1 inhibits the maturation of dendritic cells involving the nuclear factor kappa B signaling pathway in the glioma microenvironment.
Clinical & Experimental Immunology ( IF 4.6 ) Pub Date : 2020-06-09 , DOI: 10.1111/cei.13476
M He 1, 2 , X Chen 1, 2 , M Luo 2, 3 , L Ouyang 1, 2 , L Xie 1, 2 , Z Huang 2, 4 , A Liu 1, 2
Affiliation  

Recurrence and diffuse infiltration challenge traditional therapeutic strategies for malignant glioma. Immunotherapy appears to be a promising approach to obtain long‐term survival. Dendritic cells (DCs), the most specialized and potent antigen‐presenting cells (APCs), play an important part in initiating and amplifying both the innate and adaptive immune responses against cancer cells. However, cancer cells can escape from immune surveillance by inhibiting maturation of DCs. Until the present, molecular mechanisms of maturation inhibition of DCs in the tumor microenvironment (TME) have not been fully revealed. Our study showed that pretreatment with tumor‐conditioned medium (TCM) collected from supernatant of primary glioma cells significantly suppressed the maturation of DCs. TCM pretreatment significantly changed the morphology of DCs, TCM decreased the expression levels of CD80, CD83, CD86 and interleukin (IL)‐12p70, while it increased the expression levels of IL‐10, transforming growth factor (TGF)‐β and IL‐6. RNA‐Seq showed that TCM pretreatment significantly increased the gene expression level of suppressor of cytokine signaling 1 (SOCS1) in DCs. suppressor of cytokine signaling 1 (SOCS1) knock‐down significantly antagonized the maturation inhibition of DCs by TCM, which was demonstrated by the restoration of maturation markers. TCM pretreatment also significantly suppressed T cell viability and T helper type 1 (Th1) response, and SOCS1 knock‐down significantly antagonized this suppressive effect. Further, TCM pretreatment significantly suppressed p65 nuclear translocation and transcriptional activity in DCs, and SOCS1 knock‐down significantly attenuated this suppressive effect. In conclusion, our research demonstrates that TCM up‐regulate SOCS1 to suppress the maturation of DCs via the nuclear factor‐kappa signaling pathway.

中文翻译:

细胞因子信号抑制剂 1 抑制涉及神经胶质瘤微环境中核因子 kappa B 信号通路的树突细胞的成熟。

复发和弥漫性浸润对恶性胶质瘤的传统治疗策略提出了挑战。免疫疗法似乎是获得长期生存的一种有前途的方法。树突状细胞 (DC) 是最特化和最有效的抗原呈递细胞 (APC),在启动和放大针对癌细胞的先天性和适应性免疫反应方面发挥着重要作用。然而,癌细胞可以通过抑制 DC 的成熟来逃避免疫监视。直到现在,肿瘤微环境 (TME) 中 DCs 成熟抑制的分子机制尚未完全揭示。我们的研究表明,用从原代神经胶质瘤细胞上清液中收集的肿瘤条件培养基(TCM)预处理可显着抑制 DCs 的成熟。中药预处理显着改变了 DCs 的形态,中医药降低CD80、CD83、CD86和白细胞介素(IL)-12p70的表达水平,而增加IL-10、转化生长因子(TGF)-β和IL-6的表达水平。RNA-Seq 显示中药预处理显着增加 DCs 中细胞因子信号传导抑制因子 1 (SOCS1) 的基因表达水平。细胞因子信号传导抑制因子 1 (SOCS1) 的抑制显着拮抗了中药对 DCs 的成熟抑制,成熟标志物的恢复证明了这一点。中医预处理还显着抑制了 T 细胞活力和 T 辅助细胞 1 (Th1) 反应,而 SOCS1 敲低显着拮抗了这种抑制作用。此外,中药预处理显着抑制了 DCs 的 p65 核易位和转录活性,和 SOCS1 敲低显着减弱了这种抑制作用。总之,我们的研究表明,中医通过核因子-κ信号通路上调 SOCS1 以抑制 DCs 的成熟。
更新日期:2020-06-09
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