Department of Obstetrics and Gynecology, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei, Taiwan.
Endocrinology. 2010 Jan;151(1):369-79. doi: 10.1210/en.2009-0779. Epub 2009 Nov 11.
The serum lysophospholipase D activity and production of lysophosphatidic acid (LPA) increase in women with pregnancy. The effects of LPA on human placenta tissue remained unclear. We investigate the expression of LPA receptors and function of LPA in human first-trimester trophoblasts. Normal villous trophoblasts were obtained from termination of first-trimester gestation. We examined the expression of LPA receptors in primary culture of trophoblasts and the tissue. The effects of LPA on the expressions of chemokines of trophoblasts were examined using RT-PCR and enzyme immunoassay. We delineate signal pathways of LPA-inducing relevant chemokines in trophoblasts. The secretory chemokines were tested for angiogenic function using human endometrial microvascular endothelial cells and for immunological chemotaxis using decidual natural killer cells and THP-1 monocytes. The results revealed the expression of LPA1 receptors in trophoblast cells. LPA enhanced growth-regulated oncogene (GRO)-alpha, IL-8 and monocyte chemoattractant protein (MCP)-1 expressions in a time- and dose-dependent manner. Mechanistic dissection disclosed that LPA functioned mainly via the LPA1 receptor, Gi protein, various signal mediators of ERK, protein kinase C, p38, Akt, and c-Jun N-terminal kinase, and nuclear factor-kappaB pathways to secrete these chemokines. LPA-induced IL-8 protein secretion of trophoblasts enhanced permeability, migration, proliferation, and capillary tube formation of human endometrial microvascular endothelial cells. LPA-induced GRO-alpha and MCP-1 incited chemotaxis of natural killer cells and monocytes. We demonstrate that LPA mediates trophoblast cells to produce GRO-alpha, IL-8, and MCP-1 via LPA1 receptors and nuclear factor-kappaB-dependent signal pathways. Through LPA-induced chemokine production, human first-trimester trophoblast cells may regulate angiogenesis and innate immune system in early pregnancy.
血清溶血磷脂酶 D 活性和溶血磷脂酸（LPA）的产生在孕妇中增加。LPA 对人胎盘组织的影响尚不清楚。我们研究了 LPA 在人早孕绒毛膜中的受体表达和功能。从早孕终止时获得正常绒毛滋养层细胞。我们检查了原代培养的滋养层细胞和组织中 LPA 受体的表达。使用 RT-PCR 和酶免疫测定法检查 LPA 对滋养层细胞趋化因子表达的影响。我们描绘了 LPA 诱导相关趋化因子在滋养细胞中的信号通路。通过人子宫内膜微血管内皮细胞检测分泌趋化因子的血管生成功能，通过蜕膜自然杀伤细胞和 THP-1 单核细胞检测免疫趋化作用。结果显示 LPA1 受体在滋养细胞中表达。LPA 以时间和剂量依赖的方式增强生长调节癌基因（GRO）-alpha、IL-8 和单核细胞趋化蛋白（MCP）-1 的表达。机制分析表明，LPA 通过 LPA1 受体、Gi 蛋白、ERK、蛋白激酶 C、p38、Akt 和 c-Jun N 末端激酶和核因子-κB 途径发挥作用，分泌这些趋化因子。LPA 诱导的滋养层细胞 IL-8 蛋白分泌增强了人子宫内膜微血管内皮细胞的通透性、迁移、增殖和毛细血管形成。LPA 诱导的 GRO-alpha 和 MCP-1 刺激自然杀伤细胞和单核细胞的趋化作用。我们证明，LPA 通过 LPA1 受体和核因子-κB 依赖性信号通路介导滋养细胞产生 GRO-alpha、IL-8 和 MCP-1。通过 LPA 诱导的趋化因子产生，人早孕绒毛膜细胞可能在早孕期间调节血管生成和固有免疫系统。
