Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, Kanagawa.
Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
J Hypertens. 2019 Dec;37(12):2452-2460. doi: 10.1097/HJH.0000000000002208.
Preeclampsia, a pregnancy-specific syndrome, is associated with maternal systemic and placental inflammatory responses. Cell-free DNA (cfDNA) and cf-foetal DNA (cffDNA) in the blood are elevated in patients with preeclampsia and act as danger signals. Placenta-derived foetal DNA induces inflammatory responses and pregnancy complications in mice. However, whether extracellular DNA from the placenta really causes inflammatory responses remains unclear. Therefore, we investigated the effect of serum cfDNA and placental cffDNA on inflammatory responses using normal pregnant women and preeclampsia patients.
Sera were taken from normal pregnant women and preeclampsia patients, and human trophoblast cell line Sw.71 cells were treated with serum with or without toll-like receptor 9 (TLR9; a sensor of exogenous DNA) inhibitor and genome elimination reagent. For cffDNA collection, placental tissue from the participants was cultured, and the released cffDNA was administrated to Sw.71 cells.
The amount of serum cfDNA was higher in preeclampsia patients than in normal pregnant women. Treatment of preeclampsia serum stimulated inflammatory cytokine secretion, which was inhibited by a genome elimination reagent. Expression levels of TLR9 and amount of cffDNA from the placenta were higher in preeclampsia patients than of normal pregnant women. Preeclampsia-derived cffDNA increased inflammatory cytokine levels compared with normal pregnant derived cffDNA.
In human trophoblast cells, preeclampsia patient-derived cfDNA increased inflammatory cytokine levels via TLR9. Preeclampsia placenta released more cffDNA, which stimulated inflammatory cytokine. We suggest that elevated circulating cfDNA and cffDNA induces placental inflammatory responses, resulting in accelerated pathological features of preeclampsia.
子痫前期是一种与母体全身和胎盘炎症反应相关的妊娠特有的综合征。血液中的游离细胞 DNA（cfDNA）和胎儿游离 DNA（cffDNA）在子痫前期患者中升高，它们充当危险信号。胎盘来源的胎儿 DNA 可在小鼠中诱导炎症反应和妊娠并发症。然而，胎盘来源的细胞外 DNA 是否真的引起炎症反应尚不清楚。因此，我们使用正常孕妇和子痫前期患者研究了血清 cfDNA 和胎盘 cffDNA 对炎症反应的影响。
采集正常孕妇和子痫前期患者的血清，用 TLR9（外源性 DNA 的传感器）抑制剂和基因组消除试剂处理含有或不含有血清的人滋养层细胞系 Sw.71 细胞。为了收集 cffDNA，培养参与者的胎盘组织，并将释放的 cffDNA 给予 Sw.71 细胞。
子痫前期患者的血清 cfDNA 量高于正常孕妇。子痫前期患者的血清刺激炎症细胞因子分泌，用基因组消除试剂可抑制其分泌。与正常孕妇相比，子痫前期患者的 TLR9 表达水平和胎盘来源的 cffDNA 量更高。与正常孕妇来源的 cffDNA 相比，子痫前期患者来源的 cffDNA 增加了炎症细胞因子水平。
在人滋养层细胞中，子痫前期患者来源的 cfDNA 通过 TLR9 增加了炎症细胞因子水平。子痫前期胎盘释放更多的 cffDNA，刺激炎症细胞因子。我们认为，循环 cfDNA 和 cffDNA 的升高诱导胎盘炎症反应，导致子痫前期的病理特征加速。
