Lysophosphatidic Acid Up-Regulates Expression of Growth-Regulated Oncogene-α, Interleukin-8, and Monocyte Chemoattractant Protein-1 in Human First-Trimester Trophoblasts: Possible Roles in Angiogenesis and Immune Regulation

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)-α, 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-κB 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-α and MCP-1 incited chemotaxis of natural killer cells and monocytes. We demonstrate that LPA mediates trophoblast cells to produce GRO-α, IL-8, and MCP-1 via LPA1 receptors and nuclear factor-κB-dependent signal pathways. Through LPA-induced chemokine production, human first-trimester trophoblast cells may regulate angiogenesis and innate immune system in early pregnancy.