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


METHODS
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-kappaB, 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-kappaB 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.
Chen
Shee-Uan
SU
Department of Obstetrics and Gynecology, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei, Taiwan.
Chou
Chia-Hung
CH
Lee
Hsinyu
H
Ho
Chi-Hong
CH
Lin
Chung-Wu
CW
Yang
Yu-Shih
YS
D002478:Cells, Cultured; D003338:Corpus Luteum / Q000098:blood supply*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics*; D008184:Luteal Cells / Q000187:drug effects / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D016328:NF-kappa B / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D016471:Ovarian Hyperstimulation Syndrome / Q000209:etiology*; D049368:Receptors, Lysophosphatidic Acid / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
D015850:Interleukin-6; D016209:Interleukin-8; D008246:Lysophospholipids; D016328:NF-kappa B; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid