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This version published online on January 2, 2008
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-1512
A more recent version of this article appeared on March 1, 2008
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*Compound via MeSH
*Substance via MeSH

Submitted on July 9, 2007
Accepted on December 26, 2007

Lysophosphatidic acid up-regulates expression of interleukin-8 and -6 in granulosa-lutein cells through its receptors and NF-{kappa}B-dependent pathways: implications for angiogenesis of corpus luteum and ovarian hyperstimulation syndrome

Shee-Uan Chen, Chia-Hung Chou, Hsinyu Lee, Chi-Hong Ho, Chung-Wu Lin, and Yu-Shih Yang*

Department of Obstetrics and Gynecology, Department of Life Science, and Department of Pathology, National Taiwan University, Taipei, Taiwan

* To whom correspondence should be addressed. E-mail: ysyang{at}ha.mc.ntu.edu.tw.

Context: Lysophosphatidic acid (LPA) was found at significant amounts in follicular fluid of preovulatory follicle. The lysophospholipase D activity of serum from women receiving ovarian stimulation was higher than women with natural cycles. Angiogenic cytokines including interleukin (IL)-6, IL-8 and vascular endothelial growth factor (VEGF) increased in plasma and ascites of patients with ovarian hyperstimulation syndrome (OHSS). The role of LPA in ovarian follicles is unclear.

Objective: To investigate the expression of LPA receptors and function of LPA in granulosa-lutein cells.

Design: Granulosa-lutein cells were obtained from women undergoing IVF. We examined the expression of LPA receptors using RT-PCR. The effects of LPA on the expression of IL-6, IL-8 and VEGF were examined. Signal pathways of LPA were delineated. The functions of secretory angiogenic factors were tested using human umbilical vein endothelial cells (HUVEC).

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, PI3K/Akt and NF-{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 HUVEC monolayer.

Conclusions: LPA induces IL-8 and IL-6 expressions through LPA receptors and NF-{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 OHSS.
Key words: angiogenesis • granulosa-lutein cells • lysophosphatidic acid




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