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.
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