The PD‐1/PD‐L1 binding inhibitor BMS‐202 suppresses the synthesis and secretion of gonadotropins and enhances apoptosis via p38 MAPK signaling pathway
The PD‐1/PD‐L1 binding inhibitor BMS‐202 suppresses the synthesis and secretion of gonadotropins and enhances apoptosis via p38 MAPK signaling pathway
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DOI：
10.1002/ddr.21857
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发表时间：
2021-07
影响因子：
3.8
通讯作者：
Ying Jiang;Jinglin Zhang;Jingtao Qiu;S. Cui
中科院分区：
文献类型：
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作者：
Ying Jiang;Jinglin Zhang;Jingtao Qiu;S. Cui
以确定BMS-202是否会扰乱脑下垂体和生殖系统。成年雌性小鼠每隔96h腹腔注射BMS-202(2.5 mg/kg)，共4次。采用实时定量聚合酶链式反应、Western blotting、双重免疫荧光染色和放射免疫分析(RIA)等方法检测BMS-202处理后小鼠脑垂体中程序性死亡受体1(PD-1)和程序性死亡配体1(PD-L1)的表达变化。PD-1和PD-L1在小鼠脑垂体腺表达。进一步的功能研究表明，BMS-202抑制促性腺激素的合成和分泌，并延长小鼠的发情周期。此外，体内和体外裂解的caspase3(c-caspase3)蛋白水平的升高表明BMS-202诱导了细胞凋亡。此外，BMS-202对卵泡刺激素和黄体生成素mRNA水平的影响可被p38 MAPK抑制剂阻断。值得注意的是，抑制p38MAPK通路可减少BMS-202诱导的细胞凋亡。BMS-202作为一种抑制PD-1/PD-L1复合体形成的药物，扰乱了脑下垂体的正常功能。重要的是，这些结果证实了BMS-202在脑下垂体中的潜在安全性，并为其临床应用的评估提供了数据支持。
To determine whether BMS‐202 can disrupt the pituitary gland and reproductive system. BMS‐202 (2.5 mg/kg) was injected intraperitoneally into adult female mice every 96 h for four times. Real‐time polymerase chain reaction, western blotting, double immunofluorescence staining and radioimmunoassays (RIA) were used to study the expressions of programmed death receptor 1 (PD‐1) and programmed death ligand 1 (PD‐L1), and detect changes after BMS‐202 treatment in the mouse pituitary gland. PD‐1 and PD‐L1 were expressed in the mouse pituitary gland. Further functional studies demonstrated that BMS‐202 inhibited the synthesis and secretion of gonadotropins and prolonged the estrous cycle in mice. Moreover, the increases of cleaved caspase3 (c‐caspase3) protein level both in vivo and in vitro indicated that BMS‐202 induced apoptosis. Additionally, the effects of BMS‐202 on follicle‐stimulating hormone and luteinizing hormone mRNA levels were blocked by a p38 MAPK inhibitor. Of note, the inhibition of p38 MAPK pathway decreased the apoptosis induced by BMS‐202. BMS‐202, as a drug which inhibits the formation of the PD‐1/PD‐L1 complex, disrupts the normal function of the pituitary gland. Importantly, the results confirmed the potential insecurity of BMS‐202 in the pituitary gland and provided data to support the evaluation of its clinical application.