Lysophosphatidic acid up-regulates expression of interleukin-8 and-6 in granulosa-lutein cells through its receptors and nuclear factor-κB dependent pathways:: Implications for angiogenesis of corpus luteum and ovarian hyperstimulation syndrome

Context: Lysophosphatidic acid (LPA) was found at significant amounts in follicular fluid of pre-ovulatory follicle. The lysophospholipase D activity of serum from women receiving ovarian stimulation was higher than women with natural cycles. Angiogenic cytokines, including IL-6, IL-8, and vascular endothelial growth factor, increased in plasma and ascites of patients with ovarian hyperstimulation syndrome. The role of LPA in ovarian follicles is unclear. Objective: Our objective was to investigate the expression of LPA receptors and function of LPA in granulosa-lutein cells. Design: Granulosa-lutein cells were obtained from women undergoing in vitro fertilization. We examined the expression of LPA receptors using RT-PCR. The effects of LPA on the expression of IL-6, IL-8, and vascular endothelial growth factor were examined. Signal pathways of LPA were delineated. The functions of secretory angiogenic factors were tested using human umbilical vein endothelial cells. Results: The LPA1, LPA2, and LPA3 receptors' mRNA was identified in granulosa-lutein cells. LPA enhanced IL-8 and IL-6 expressions in a dose- and time-dependent manner. LPA functioned via LPA receptors, Gi protein, MAPK/ERK, p38, phosphatidylinositol 3-kinase/Akt, and nuclear factor-kappa B, and transactivation of epidermal growth factor receptor. LPA induced IL-8 and IL-6 through different pathways. LPA-induced IL-8 and IL-6 increased permeability of human umbilical vein endothelial cell monolayer. Conclusions: LPA induces IL-8 and IL-6 expressions through LPA receptors and nuclear factor-kappa B dependent pathways in granulosa-lutein cells. The LPA in preovulatory follicles may play a role in the angiogenesis of corpus luteum. Large amounts of LPA-induced IL-8 and IL-6 from multiple corpora luteae of stimulated ovaries may be one of the pathophysiological causes of ovarian hyperstimulation syndrome.