程序性细胞死亡配体 1/程序性细胞死亡受体 1 通路通过调节脊髓炎症细胞因子介导妊娠诱导的镇痛。
The Programmed Cell Death Ligand-1/Programmed Cell Death-1 Pathway Mediates Pregnancy-Induced Analgesia via Regulating Spinal Inflammatory Cytokines.
机构信息
From the Department of Anesthesiology, Xiangya Hospital, Central South University Changsha, Changsha, China.
Departments of Anesthesiology, Second Xiangya Hospital.
出版信息
Anesth Analg. 2021 Nov 1;133(5):1321-1330. doi: 10.1213/ANE.0000000000005737.
BACKGROUND
The maternal pain threshold gradually increases during pregnancy, especially in late pregnancy. A series of mechanisms underlying pregnancy-induced analgesia have been reported. However, these mechanisms are still not completely clear, and the underlying molecular mechanisms need further investigation. We examined the relationship between the antinociceptive effect and the expression level of programmed cell death ligand-1 (PD-L1) during pregnancy and further observed the changes in pain thresholds and expression levels of cytokines in late-pregnant mice before and after blockade of PD-L1 or programmed cell death-1 (PD-1).
METHODS
Part 1: Female mice were assigned to 3 groups (nonpregnant, late-pregnant, and postpartum). Part 2: Late-pregnant mice were assigned to 3 treatment groups (control [phosphate buffer solution], RMP1-14 [mouse anti-PD-1 antibody], and soluble PD-1 [sPD-1]). Behavioral testing (mechanical and thermal) and tissue (serum and spinal cord) analysis were performed on all groups. PD-L1, interleukin (IL)-10, tumor necrosis factor-α (TNF-α), and IL-6 expression levels in tissue were examined via reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blot analysis.
RESULTS
The mechanical and thermal pain thresholds were significantly increased in late pregnancy and decreased after delivery. PD-L1 expression was also elevated in late pregnancy and decreased after delivery. In addition, in the late stage of gestation, the maternal inflammatory microenvironment was dominated by anti-inflammatory factors. After administration of RMP1-14 or sPD-1, the pain thresholds of late-pregnant mice were significantly reduced. In late-pregnant mice, the high level of IL-10 was obviously reduced, and the low levels of TNF-α and IL-6 were elevated.
CONCLUSIONS
The PD-L1/PD-1 pathway mediates pregnancy-induced analgesia, partially via the regulation of cytokines.
背景
母体的疼痛阈值在怀孕期间逐渐升高，尤其是在妊娠晚期。已经报道了一系列与妊娠相关的镇痛相关的机制。然而，这些机制仍不完全清楚，其潜在的分子机制需要进一步研究。我们研究了妊娠期间抗伤害作用与程序性细胞死亡配体 1（PD-L1）表达水平之间的关系，并进一步观察了阻断 PD-L1 或程序性细胞死亡-1（PD-1）前后晚期妊娠小鼠的疼痛阈值和细胞因子表达水平的变化。
方法
第 1 部分：将雌性小鼠分为 3 组（未孕、妊娠晚期和产后）。第 2 部分：将妊娠晚期小鼠分为 3 个治疗组（对照组[磷酸盐缓冲液]、RMP1-14[抗 PD-1 抗体]和可溶性 PD-1[sPD-1]）。对所有组进行行为测试（机械和热）和组织（血清和脊髓）分析。通过逆转录-聚合酶链反应（RT-PCR）、酶联免疫吸附测定（ELISA）和 Western blot 分析检测组织中 PD-L1、白细胞介素（IL）-10、肿瘤坏死因子-α（TNF-α）和 IL-6 的表达水平。
结果
妊娠晚期机械和热痛阈值显著升高，分娩后降低。PD-L1 的表达也在妊娠晚期升高，分娩后降低。此外，在妊娠晚期，母体炎症微环境以抗炎因子为主。给予 RMP1-14 或 sPD-1 后，妊娠晚期小鼠的痛阈值明显降低。在妊娠晚期小鼠中，高水平的 IL-10 明显降低，而 TNF-α 和 IL-6 的水平降低。
结论
PD-L1/PD-1 途径介导妊娠相关的镇痛作用，部分通过调节细胞因子。
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