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

Abstract

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.

TNF-α alters the inflammatory secretion profile of human first trimester placenta

“…49 Both, IL-8 and CCL2 derived from human villous first trimester trophoblasts were shown to enhance multistep processes of angiogenesis such as permeability, migration, proliferation, and capillary tube formation of human endometrial microvascular endothelial cells. 50 Although abundant IL-6 and IL-8 secretion under basal conditions is in good agreement with other studies, results from our explant experiments suggest that secretion of both IL-6 and IL-8 is not considerably affected by exogenous TNF-α in human first trimester placenta. Interestingly, IL-6 and IL-8 secretion by first trimester placental explants is also not affected by para-Nonylphenol, a ubiquitous environmental contaminant described to significantly increase placental secretion of inflammatory cytokines such as IFN-γ, IL-1β, and TNF-α.…”

Differential roles of inflammation and apoptosis in initiation of mid-gestational abortion in malaria-infected C57BL/6 and A/J mice

“…As shown here, conceptus chemokine gene expression is clearly different between the two mouse strains, with A/J mice overall tending to have higher and/or more sustained expression of potentially pivotal chemoattractants ( Ccl2 and Ccl4 ) for monocytes, cell types found to accumulate in the A/J conceptus. The potential sources for these chemokines are many; Ccl2 is secreted by monocytes and epithelia, including first trimester [49] and term human syncytiotrophoblast, albeit strictly in the context of cytomegalovirus infection in the latter [50]. Although CCL2 is not expressed by primary human syncytiotrophoblast exposed to cytoadherent P. falciparum [6], and is restricted to maternal macrophages and intravillous stromal cells in the P. falciparum -infected term human placenta [4], it is apparently produced by mid-gestation murine trophoblast exposed to P. chabaudi AS, irrespective to mouse strain.…”

Regulation of Mammalian Physiology, Development, and Disease by the Sphingosine 1-Phosphate and Lysophosphatidic Acid Receptors

“…Interestingly, although LPA 3 is highly expressed in oviduct, placenta, and uterus, it is absent from the ovary, where LPA 4 is highly expressed in both human and mouse tissues 152,348 . In humans, endometrial stroma and first trimester trophoblasts expressed only LPA 1 mRNA, and LPA signaling induced in vitro IL-8 production, angiogenesis, and immune cell migration 349,350 . These studies demonstrate that both maternal and fetal LPAR signaling cooperate to ensure successful pregnancy.…”