Laboratory for Prenatal Medicine, Department of Biomedicine, University Hospital Basel , Basel , Switzerland.
Department of Obstetrics and Gynecology, University Hospital Basel , Basel , Switzerland.
Front Immunol. 2014 Apr 15;5:173. doi: 10.3389/fimmu.2014.00173. eCollection 2014.
Human pregnancy is accompanied by a mild systemic inflammatory response, which includes the activation of monocytes circulating in maternal blood. This response is exaggerated in preeclampsia, a placental-dependent disorder specific to human pregnancies. We and others showed that placental syncytiotrophoblast membrane microparticles (STBM) generated in vitro from normal placentas stimulated peripheral blood monocytes, which suggest a contribution of STBM to the systemic maternal inflammation. Here, we analyzed the inflammatory potential of STBM prepared from preeclamptic placentas on primary monocytes and investigated the mode of action in vitro. STBM generated in vitro by placental villous explants of normal or preeclamptic placentas were co-incubated with human peripheral blood monocytes. In some cases, inhibitors of specific cellular functions or signaling pathways were used. The analysis of the monocytic response was performed by flow cytometry, enzyme-linked immunoassays, real-time PCR, and fluorescence microscopy. STBM derived from preeclamptic placentas up-regulated the cell surface expression of CD54, and stimulated the secretion of the pro-inflammatory interleukin (IL)-6 and IL-8 in a similar, dose-dependent manner as did STBM prepared from normal placentas. STBM bound to the cell surface of monocytes, but phagocytosis was not necessary for activation. STBM-induced cytokine secretion was impaired in the presence of inhibitors of toll-like receptor (TLR) signaling or when nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation was blocked. Our results suggest that the inflammatory reaction in monocytes may be initiated by the interaction of STBM with TLRs, which in turn signal through NF-κB to mediate the transcription of genes coding for pro-inflammatory factors.
人类妊娠伴随着轻微的全身炎症反应，包括母体血液中循环单核细胞的激活。这种反应在子痫前期中被夸大，子痫前期是一种与人类妊娠特异性相关的胎盘依赖性疾病。我们和其他人已经表明，体外从正常胎盘产生的胎盘合体滋养层膜微粒（STBM）刺激外周血单核细胞，这表明 STBM 对全身母体炎症有一定的贡献。在这里，我们分析了来自子痫前期胎盘的 STBM 对原代单核细胞的炎症潜能，并研究了体外的作用模式。正常或子痫前期胎盘绒毛外植体体外生成的 STBM 与人类外周血单核细胞共孵育。在某些情况下，使用特定细胞功能或信号通路的抑制剂。通过流式细胞术、酶联免疫吸附试验、实时 PCR 和荧光显微镜分析单核细胞反应。来自子痫前期胎盘的 STBM 上调了 CD54 的细胞表面表达，并以类似于正常胎盘制备的 STBM 的方式刺激促炎细胞因子白细胞介素 (IL)-6 和 IL-8 的分泌，呈剂量依赖性。STBM 与单核细胞的细胞表面结合，但吞噬作用对于激活不是必需的。在存在 Toll 样受体 (TLR) 信号转导抑制剂或核因子 kappa-轻链增强子的激活 B 细胞 (NF-κB) 激活被阻断的情况下，STBM 诱导的细胞因子分泌受损。我们的结果表明，单核细胞中的炎症反应可能是由 STBM 与 TLRs 的相互作用引发的，TLRs 通过 NF-κB 信号转导介导编码促炎因子的基因转录。
