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氧化苦参碱介导的树突状细胞成熟导致 FOXP3+/CD4+Treg 细胞的激活和肺癌细胞顺铂耐药性的逆转。

Oxymatrine‑mediated maturation of dendritic cells leads to activation of FOXP3+/CD4+ Treg cells and reversal of cisplatin‑resistance in lung cancer cells.

机构信息

Division of Pulmonary and Critical Care, Department of Internal Medicine, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 501630, P.R. China.

Department of Otolaryngology‑Head and Neck Surgery, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 501630, P.R. China.

出版信息

Mol Med Rep. 2019 May;19(5):4081-4090. doi: 10.3892/mmr.2019.10064. Epub 2019 Mar 20.

Abstract

The dendritic cell (DC)‑regulatory T (Treg) system serves a leading role in the immunosuppression of the tumor microenvironment, which is not conducive to radiotherapy and chemotherapy treatment for lung cancer. The present study aimed to investigate the effect of oxymatrine (OMT) on the DC‑Treg system in the tumor microenvironment in vitro and to examine its mechanism. The expressions of CD83 antigen, T‑lymphocyte activation antigen CD86, CD11 antigen‑like family member C and major histocompatibility complex II in DCs were increased upon treatment with 1 mg/ml OMT, as detected by flow cytometry. Following pretreatment with OMT, the DCs mediated the forkhead box protein P3 overexpression in primitive cluster of differentiation 4+ T cells at the protein and mRNA expression levels. The expression levels of anti‑inflammatory factors, including interleukin (IL)‑10, tumor growth factor‑β, IL‑35, and pro‑inflammatory cytokines, including interferon‑γ, IL‑12 and IL‑2, in the co‑culture supernatant were increased as measured by ELISA. When DCs and DC‑Tregs were co‑cultured with cisplatin‑resistant A549 cells, the proportion of apoptosis in the co‑culture groups was increased under treatment with cisplatin, which was detected by Annexin V/propidium Iodide staining and western blotting. The present results suggested that OMT may promote the maturation of DCs, mediate the differentiation of T cells into Treg cells, and reverse the resistance of tumor cells to cisplatin in vitro. It was suggested that OMT is an important adjunct to chemotherapy through the regulation of antitumor responses.

摘要

树突状细胞(DC)-调节性 T(Treg)系统在肿瘤微环境的免疫抑制中起主要作用,这不利于肺癌的放化疗治疗。本研究旨在探讨氧化苦参碱(OMT)对体外肿瘤微环境中 DC-Treg 系统的影响及其机制。通过流式细胞术检测到,当用 1mg/ml OMT 处理时,DC 中 CD83 抗原、T 淋巴细胞激活抗原 CD86、CD11 抗原样家族成员 C 和主要组织相容性复合体 II 的表达增加。经 OMT 预处理后,DC 在原始簇分化 4+T 细胞中介导叉头框蛋白 P3 的过表达,在蛋白和 mRNA 表达水平上。ELISA 检测到共培养上清液中抗炎因子(包括白细胞介素(IL)-10、肿瘤生长因子-β、IL-35)和促炎细胞因子(包括干扰素-γ、IL-12 和 IL-2)的表达水平增加。当 DC 和 DC-Tregs 与顺铂耐药 A549 细胞共培养时,顺铂处理后共培养组中的细胞凋亡比例增加,通过 Annexin V/碘化丙啶染色和 Western blot 检测到。本研究结果表明,OMT 可能促进 DC 的成熟,介导 T 细胞向 Treg 细胞分化,并逆转肿瘤细胞对顺铂的耐药性。这表明 OMT 通过调节抗肿瘤反应,是化疗的重要辅助手段。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9257/6471056/69170591b541/MMR-19-05-4081-g00.jpg

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