Phospholipase A2 isozymes in pregnancy and parturition

doi:10.1016/j.plefa.2003.04.001

Prostaglandins, Leukotrienes and Essential Fatty Acids

Volume 70, Issue 2, February 2004, Pages 87-100

https://doi.org/10.1016/j.plefa.2003.04.001 Get rights and content

Abstract

Mammalian cells contain several structurally different phospholipase (PLA₂) enzymes that exhibit distinct localisation, function and mechanisms of regulation. PLA₂ isozymes have been postulated to play significant roles in the parturition process. Both secretory and cytosolic PLA₂ isozymes have been identified in human gestational tissues, and there is differential expression of these PLA₂ isozymes in human fetal membranes and placenta obtained at preterm and term. The aims of this commentary are: (1) to review recent data concerning the expression, role and regulation of PLA₂ isozymes in human gestational tissues; and (2) to present novel data demonstrating the regulation of PLA₂ isozymes in human gestational tissues by nuclear factor-kappa B (NF-κB) and peroxisome proliferator-activated receptor (PPAR)-g.

Introduction

During pregnancy, multiple pathways are established for transfer of information between mother and foetus that are essential for foetal growth and development. These pathways involve the formation and release of endocrine, paracrine and autocrine factors. One such pathway generating signals that may be interpreted by extracellular and intracellular sensors involves the metabolism of cell membrane phospholipids. The formation of phospholipid-derived mediators (PDMs) proceeds by a multiple enzyme pathway that is initiated by lipolytic enzymes that includes phospholipases A₁, A₂, C and D. These PDMs may act either as primary mediators (e.g., lysophosphatides, themselves manifesting biological activity), or may act as precursors for the formation of secondary mediators (such as the eicosanoids prostaglandins and leukotrienes). Prostaglandins of the 2-series are of major importance in parturition and have been implicated in the regulation of many aspects of cell function and in the processes of mammalian pregnancy and parturition. They are recognised as factors that promote myometrial contractions, cervical dilatation and membrane rupture [1].

Prostaglandins are formed via the action of multiple enzyme pathways, involving phospholipase (PLA₂) and cyclooxygenase (COX) isozymes. Through the activity of one or more PLA₂ enzymes, non-esterified arachidonic acid is released from membrane phospholipids such as phosphatidylinositol and phosphatidylethanolamine. COX are bifunctional enzymes that catalyses the first two steps in the biosynthesis of prostaglandins from the substrate arachidonic acid (reviewed in [2]).

Three PLA₂ isozymes have been identified: the intracellular isozyme—cytosolic PLA₂ (cPLA₂), and the secretory PLA₂ (sPLA₂) enzymes sPLA₂-IIA and sPLA₂-V. Their expression in human gestational tissues have been partially characterised and will be discussed in ensuing sections.

Section snippets

Phospholipase A₂ isozymes

PLA₂ represents a ubiquitous family of esterases that hydrolyse the sn-2 acyl ester bond of 1,2 diacyl-sn-3 glycerophospholipids, thereby liberating equimolar amounts of 1-acyl lysophosphatide and free fatty acid [3]. The lysophospholipids may serve as precursors in the generation of platelet activating factor (PAF) or may themselves be pro-inflammatory mediators. As arachidonic acid is predominantly found esterified in the sn-2 position of membrane phospholipids, PLA₂ contributes significantly

Secretory PLA₂

Secretory PLA₂s are a large family of low molecular weight (14–19 kDa) extracellularly active enzymes (reviewed in [6]). These enzymes are characterised by six or seven intramolecular disulphide bonds, that give them a rigid tertiary structure that is resistant to heat and acid inactivation but sensitive to inactivation by disulphide reducing agents. sPLA₂s display optimal enzymatic activity in the presence of millimolar concentrations of calcium and neutral to alkaline pH. The sPLA₂ family of

Cytosolic PLA₂

The cPLA₂ (also referred to as type IV PLA₂) family are a high molecular weight (85 kDa) PLA₂s that differs from other cellular phospholipases by their specificity for esterified arachidonic acid in the sn-2 position. Currently, three isozymes have been identified: cPLA₂α, cPLA₂β, and cPLA₂γ [41], [37]. Although the three cPLA₂ isozymes share high homology, they differ markedly in their affinity for arachidonyl substrates. cPLA₂α is the best characterised and the most relevant for intracellular

Secretory PLA₂ in human labour and delivery

In human gestational tissues, most studies have focused on the presence of sPLA₂-IIA, although other PLA₂ enzymes have also been identified (reviewed in [55], [56]). Much of the data that has previously been published on the role of sPLA₂ in human parturition requires considered interpretation. Previous studies have quantified net PLA₂ enzymatic activity ex situ where the contribution made by the individual PLA₂ isozymes is difficult to establish and dependent on the specificity of inhibitors

Transcriptional regulation of phospholipases in human gestational tissues

Two transcription factors, NF-κB and peroxisome proliferator-activated receptor (PPAR)-γ, have been demonstrated to positively and negatively regulate the inflammatory response in non-gestational tissues, respectively (reviewed in [92], [93]). Furthermore, the promoter region for the sPLA₂ and cPLA₂α gene contain NF-κB and PPAR-γ binding sites. However, not much is known about the transcription factors involved in regulation of PLA₂ isozymes in human reproductive tissues. Therefore, studies in

Summary

The aim of this review was to highlight recent advances in establishing the role of PLA₂ isozymes in human pregnancy and, in particular, labour and delivery. Available evidence confirms the importance of cytosolic PLA₂ isozymes to the labour-associated increase in eicosanoid formation. In addition to the well-established role of this family of lipolytic enzymes in the liberation of arachidonic acid from membrane phospholipids, there is increasing evidence that the secretory forms of PLA₂ may

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Phospholipase A2 isozymes in pregnancy and parturition

Abstract

Introduction

Section snippets