Synthesis and release of eicosanoids by amnion in response to autocrine paracrine effectors may be involved in the onset of parturition in humans. The signal transduction pathways by which these effectors act are ill-defined, but potentially should involve regulation of key enzymes in the arachidonic acid cascade. We and others have recently shown that cytokines, growth factors and phorbol esters stimulate amnion PGE2 synthesis in concert with induction of a novel isoform of prostaglandin H synthase (PGHS-2). This enzyme does, however, require a source of substrate arachidonic acid, therefore teleologically, increased activity of phospholipase A2 (PLA2) activity should be expected to occur in parallel. Previous findings that the activity of amnion PLA2 activity increased throughout gestation, but did not change further at parturition need to be critically reevaluated as nonhomologous PLA2, isoforms both secreted (sPLA2) and cytosolic (cPLA2) have been recently demonstrated. These isoforms have distinct substrate specificities and differential regulation. Increasing calcium concentrations and phosphorylation will translocate cPLA2 to cell membranes, cause association with substrate and hence increase PLA2 activity. Certain cytokines can also stimulate de novo synthesis of cPLA2 making it a key transducer in the hormonal regulation of eicosanoid synthesis.
We aim to: 1. Identify isoforms of PLA2 present in human fetal membranes, study their expression, immunohistochemical distribution and determine changes in expression, distribution and activity of PLA2 isoforms which occur with term or preterm labor in amnion tissue. 2, Determine the effects of the sex steroids estrogen and progesterone, growth factors, cytokines and phorbol esters on PLA2 activity and its relationship to PGHS expression and PGE2 synthesis in amnion-derived WISH cells. Both total cellular activity of PLA2 isoforms and their subcellular distribution when stimulated by agonist will be determined. 3. Determine the effects of sex steroids, growth factors, cytokines and phorbol esters on phosphorylation of cPLA2 and whether phosphorylation alters both the subcellular distribution and activity of cPLA2. 4. Examine the expression of cPLA2 mRNA in amnion tissue in term and preterm labor, determine the time course of induction of cPLA2 mRNA in WISH cells when stimulated by various agonists and its relationship to cPLA2 activity and study transcriptional, translation or posttranlational control of cPLA2. This study will provide novel data on the isoforms of PLA2 present in amnion and fetal membranes and their regulation. It will allow development of a more integrated picture of the control of eicosanoid synthesis during labor especially towards the role of the sex steroids and cytokines.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD031514-01A1
Application #
2204075
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1995-02-01
Project End
1999-01-31
Budget Start
1995-02-01
Budget End
1996-01-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Guo, Chunming; Wang, Wangsheng; Liu, Chao et al. (2014) Induction of PGF2? synthesis by cortisol through GR dependent induction of CBR1 in human amnion fibroblasts. Endocrinology 155:3017-24
Guo, Chunming; Li, Cun; Myatt, Leslie et al. (2013) Sexually dimorphic effects of maternal nutrient reduction on expression of genes regulating cortisol metabolism in fetal baboon adipose and liver tissues. Diabetes 62:1175-85
Wang, Weihua; Guo, Chunming; Li, Wenjiao et al. (2012) Involvement of GR and p300 in the induction of H6PD by cortisol in human amnion fibroblasts. Endocrinology 153:5993-6002
Guo, C M; Kasaraneni, N; Sun, K et al. (2012) Cross talk between PKC and CREB in the induction of COX-2 by PGF2? in human amnion fibroblasts. Endocrinology 153:4938-45
Guo, Chunming; Yang, Zhen; Li, Wenjiao et al. (2008) Paradox of glucocorticoid-induced cytosolic phospholipase A2 group IVA messenger RNA expression involves glucocorticoid receptor binding to the promoter in human amnion fibroblasts. Biol Reprod 78:193-7
Yang, Zhen; Guo, Chunming; Zhu, Ping et al. (2007) Role of glucocorticoid receptor and CCAAT/enhancer-binding protein alpha in the feed-forward induction of 11beta-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts. J Endocrinol 195:241-53
Sun, Kang; Brockman, Diane; Campos, Begona et al. (2006) Induction of surfactant protein A expression by cortisol facilitates prostaglandin synthesis in human chorionic trophoblasts. J Clin Endocrinol Metab 91:4988-94
Sun, K; Qu, X; Gao, L et al. (2006) Dexamethasone fails to inhibit the induction of cytosolic phospholipase A(2) expression by interleukin-1beta in cultured primary human amnion fibroblasts. Placenta 27:164-70
Sun, Kang; Myatt, Leslie (2003) Enhancement of glucocorticoid-induced 11beta-hydroxysteroid dehydrogenase type 1 expression by proinflammatory cytokines in cultured human amnion fibroblasts. Endocrinology 144:5568-77
Meadows, Juliana W; Eis, Annie L W; Brockman, Diane E et al. (2003) Expression and localization of prostaglandin E synthase isoforms in human fetal membranes in term and preterm labor. J Clin Endocrinol Metab 88:433-9

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