Finasteride Enhances the Generation of Human Myeloid-Derived Suppressor Cells by Up-Regulating the COX2/PGE2 Pathway.
Finasteride Enhances the Generation of Human Myeloid-Derived Suppressor Cells by Up-Regulating the COX2/PGE2 Pathway.
复制标题
非那雄胺通过上调 COX2/PGE(2) 途径增强人骨髓源性抑制细胞的生成
DOI：
10.1371/journal.pone.0156549
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Fu Y
中科院分区：
文献类型：
--
作者：
Zhang S;Wu K;Liu Y;Lin Y;Zhang X;Zhou J;Zhang H;Pan T;Fu Y
髓源性抑制细胞（MDSCs）在许多情况下，如肿瘤、感染、自身免疫性疾病和移植，是调节免疫系统的关键因素。与MDSCs在肿瘤和感染中的有害作用相反，具有抑制功能的MDSCs现在被证明具有抑制自身免疫反应和促进移植耐受性的有益潜力。因此，扩增MDSCs可能是治疗许多疾病的一种有希望的治疗策略。在这项研究中，我们的目标是确定fda批准的药物，可以帮助扩大功能性MDSCs。我们基于体外人MDSCs分化系统对fda批准的药物进行了高通量筛选（HTS），并确定非那雄胺（FIN）对人MDSCs的生成具有最佳效力。fin诱导的MDSCs在表面表型、形态、免疫抑制功能和相关基因表达方面与单核细胞MDSCs非常相似。接下来，我们旨在确定FIN的作用机制，发现FIN通过增强COX2启动子的活性，上调COX2/PGE2通路，诱导MDSCs的扩增。此外，COX2抑制剂吲哚美辛（indomethacin， IND）的使用可以消除FIN的作用。基于这些结果，我们认为FIN可以在未来的MDSCs扩增中找到应用。进一步开发fin样化合物可能是产生功能性MDSCs用于各种免疫疾病的免疫抑制治疗的新策略。
Myeloid-derived suppressor cells (MDSCs) have been known to be a key factor in the regulation of the immune system under numerous conditions such as tumors, infections, autoimmune diseases, and transplantations. In contrast to the proposed deleterious role of MDSCs in tumors and infections, MDSCs with their suppressive function are now proved to have the beneficial potential of suppressing the autoimmune response and promoting tolerance to transplantation. Therefore, the expansion of MDSCs could be a promising therapeutic strategy for many diseases. In this study, we aimed to identify FDA-approved drugs that could aid in the expansion of functional MDSCs. We performed a high-throughput screening (HTS) of FDA-approved drugs based on the in vitro human MDSC-differentiation system and identified finasteride (FIN) to have the best potency to aid the generation of human MDSCs. The FIN-induced MDSCs were quite similar to monocytic MDSCs with regard to their surface phenotype, morphology, immunosuppressive function, and related gene expression. Next, we aimed to determine the mechanism of action of FIN and found that FIN induced the expansion of MDSCs through up-regulation of the COX2/PGE2 pathway by enhancing the activity of COX2 promoter. In addition, the administration of indomethacin (IND), a COX2 inhibitor, abrogated the effect of FIN. Based on these results, we suggested that FIN could find applications in the future in the expansion of MDSCs. Further development of FIN-like compounds could be a novel strategy for generating functional MDSCs for immunosuppressive therapies in various immune disorder conditions.