Prostaglandins, Leukotrienes and Essential Fatty Acids
Phospholipase A2 isozymes in pregnancy and parturition
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
References (111)
- et al.
Arachidonic acid oxygenation by COX-1 and COX-2
J. Biol. Chem.
(1999) - et al.
The importance of phospholipase A2 in prostaglandin biosynthesis
Biochem. Pharmacol.
(1976) - et al.
Presence of pancreatic-type phospholipase A2 mRNA in rat gastric mucosa and lung
Biochem. Biophys. Acta
(1989) - et al.
Mammalian phospholipase A2mediators of inflammation, proliferation and apoptosis
Prog. Lipoid Res.
(2001) - et al.
Cloning and recombinant expression of phospholipase A2 present in rheumatoid arthritic synovial fluid
J. Biol. Chem.
(1989) - et al.
Cloning and recombinant expression of a novel human low molecular weight Ca2+-dependent phospholipase A2
J. Biol. Chem.
(1994) - et al.
Structure and properties of a human non-pancreatic phospholipase A2
J. Biol. Chem.
(1989) - et al.
Transcriptional regulation of inflammatory secreted phospholipases A2
Biochem. Biophys. Acta
(2000) - et al.
Inflammatory factors stimulate expression of group II phospholipase A2 in rat cultured astrocytes
J. Biol. Chem.
(1991) - et al.
Group II phospholipase A2 in invasive gastric cancer cell line is induced by interleukin-6
Biochem. Biophys. Res. Commun.
(1994)
Group II phospholipase A2 mRNA synthesis is stimulated by two distinct mechanisms in rat vascular smooth muscle cells
FEBS Lett.
Interleukin-1α stimulates prostaglandin biosynthesis in serum-activated mesengial cells by induction of a non-pancreatic (type II) phospholipase A2
J. Biol. Chem.
Molecular mechanisms involved in the regulation of prostaglandin biosynthesis by glucocorticoids
Biochem. Pharmacol.
Roles of secretory phospholipase A2 in inflammatory disease and trauma
Biochem. Biophys. Acta
Phospholipase A2—a mediator between proximal and distal effectors of inflammation
Immunol. Today
The functions of five distinct mammalian phospholipase A2s in regulating arachidonic acid release—type IIA and type V secretory phospholipase A2s are functionally redundant and act in concert with cytosolic phospholipase A2
J. Biol. Chem.
Genes encoding multiple forms of phospholipase A2 are expressed in rat brain
Neurosci. Lett.
Cloning, chromosomal mapping, and expression of a novel human secretory phospholipase A2
J. Biol. Chem.
Cloning and characterization of novel mouse and human secretory phospholipase A2s
J. Biol. Chem.
Increasing molecular diversity of secreted phospholipases A2 and their receptors and binding proteins
Biochem. Biophys. Acta
Cloning and expression of a membrane receptor for secretory phospholipases A2
J. Biol. Chem.
Distribution of the phospholipase A2 receptor messenger RNA in human gestational tissues
Placenta
Localisation and regulation of cytosolic PLA2
Biochem. Biophys. Acta
A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP
Cell
Cytosolic phospholipase A2 gene in human and ratchromosomal localisation and polymorphic markers
Genomics
Detection of arachidonoyl-selective phospholipase A2 in human neutrophil cytosol
Biochem. Biophys. Acta
Isolation of promoter for cytosolic phospholipase A2 (cPLA2)
Biochem. Biophys. Acta
Interleukin-1α induces the accumulation of cytosolic phospholipase A2 and the release of prostaglandin E2 in human fibroblasts
J. Biol. Chem.
Interleukin-1 beta induces the synthesis and activity of cytosolic phospholipase A2 and the release of prostaglandin E2 in human amnion-derived WISH cells
Prostaglandins
Properties and regulation of cytosolic phospholipase A2
J. Biol. Chem.
Mammalian lysophospholipases
Biochem. Biophys. Acta
Specific physiological roles of cytosolic phospholipase A2 as defined by gene knockouts
Biochem. Biophys. Acta
Secretory phospholipases and membrane polishing
Placenta
Type II phospholipase A2 in human gestational tissuessubcellular distribution of placental immuno- and catalytic activity
Biochem. Biophys. Acta
Relative abundance of human placental phospholipase A2 messenger RNA in late pregnancy
Prostaglandins
Expression of a common cellular phospholipase A2 by human intrauterine tissues
Prostaglandins
Type II phospholipase A2 in human gestational tissuesextractable immuno- and enzymatic activity in fetal membranes
Biochem. Biophys. Acta
The expression of phospholipase A2 and lipocortins (annexins) I, II and V in human fetal membranes and placenta in association with labour
Prostaglandins
Secretory type II phospholipase and PLA2 enzymatic activity in human gestational tissues before, during and after spontaneous-onset labour at term
Placenta
Localisation of type II phospholipase A2 messenger RNA and immunoreactivity in human placenta and fetal membranes
Placenta
Elevations of group II phospholipase A2 concentrations in serum and amniotic fluid in association with preterm labour
Am. J. Obstet. Gynaecol.
Immunoreactive type II phospholipase A2 levels in human preterm gestational tissues
Placenta
Human neutrophils store type II 14 kD phospholipase A2 in granules and secrete active enzyme in response to soluble stimuli
Biochem. Biophys. Res. Commun.
Transcellular prostaglandin production following mast cell activation is mediated by proximal secretory PLA2 and distal PGHS-1
J. Biol. Chem.
Arachidonic acid metabolites in pregnant rat uterus
Prostag. Leukot. Essent. Fatty Acids
Antisense oligonucleotide inhibition of type II phospholipase A2 expression, release and activity in vitro
Placenta
Novel proliferative effect of phospholipase A2 in Swiss 3T3 cells via specific binding site
J. Biol. Chem.
Contraction of guinea pig lung parenchyma by pancreatic type phospholipase A2 via its specific binding site
FEBS Lett.
Migration of vascular smooth muscle cells by phospholipase A2 via specific binding sites
Biochim. Biophys. Acta
Pancreatic-type phospholipase A2 stimulates prostaglandin synthesis in mouse osteoblastic cells (MC3T3-E1) via a specific binding site
J. Biol. Chem.
Cited by (72)
Nasopharyngeal SARS-CoV-2 load and perinatal outcomes after maternal infection diagnosed close to delivery
2023, Journal of Gynecology Obstetrics and Human ReproductionLysophosphatidic acid production from lysophosphatidylcholine by lysophospholipase D activity of autotaxin in plasma of women with normal and adverse pregnancies
2022, Prostaglandins and Other Lipid MediatorsCitation Excerpt :For instance, the total plasma level of phospholipids having an n-3 polyunsaturated fatty acyl group that is essential for establishment of the central nervous system changes during pregnancy [4–6]. Phospholipase A2 (PLA2) isozymes have been postulated to play significant roles in parturition [7], but its roles in the maintenance of pregnancy remain largely unclear. Secretory PLA2 IIA and V are known to be released from the human placenta into the fetal blood circulation [8], generating potential lysophospholipid mediators.
Role of leptin as a link between metabolism and the immune system
2017, Cytokine and Growth Factor ReviewsParturition
2015, Knobil and Neill's Physiology of Reproduction: Two-Volume SetSlit2 is decreased after spontaneous labour in myometrium and regulates pro-labour mediators
2014, Journal of Reproductive Immunology