You are on page 1of 12

REPRODUCTION

REVIEW

Going into labor and beyond: phospholipase A2 in pregnancy
Carolin Besenboeck, Silvija Cvitic, Uwe Lang, Gernot Desoye and Christian Wadsack
Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
Correspondence should be addressed to C Wadsack; Email: christian.wadsack@medunigraz.at

Abstract
The phospholipase A2 (PLA2) family is a very diverse group of enzymes, all serving in the cleavage of phospholipids, thereby releasing
high amounts of arachidonic acid (AA) and lysophospholipids. AA serves as a substrate for prostaglandin production, which is of
special importance in pregnancy for the onset of parturition. Novel research demonstrates that PLA2 action affects the immune
response of the mother toward the child and is therefore probably implied in the tolerance of the fetus and prevention of miscarriage.
This review presents data on the biochemical and enzymatic properties of PLA2 during gestation with a special emphasis on its role
for the placental function and development of the fetus. We also critically discuss the possible pathophysiological significance of
PLA2 alterations and its possible functional consequences. These alterations are often associated with pregnancy pathologies such as
preeclampsia and villitis or pregnancy complications such as obesity and diabetes in the mother as well as preterm onset of labor.
Reproduction (2016) 151 R91–R102

Introduction to the PLA2 superfamily
The phospholipase A2 (PLA2) superfamily consists
of enzymes of very diverse nature with respect to
their cellular localization, dependency on cofactors,
and substrate preference. As a consequence of this
diversity, PLA2 enzymes have been implicated in various
biochemical processes (Kudo & Murakami 2002, Quach
et  al. 2014). Common to all these enzymes, however,
is that all of them catalyze the hydrolysis of an ester
bond at the second carbon group (sn-2 position) of a
glycerophospholipid releasing a free fatty acid (FFA)
and a lysophospholipid. The fatty acid freed from the
lipid backbone is in many cases arachidonic acid
(AA; C20:4), which is used within the cyclooxygenase
(COX) or the lipoxygenase (LOX) pathway to form
prostaglandin (PG) and thromboxane or leukotriene
respectively. These metabolites are important mediators
of inflammation. However, more importantly, eicosanoic
lipid mediators generated within the COX pathway are
crucial for the coordinated and timely onset of labor.
Moreover, PGs are essential to ovulation, fertilization,
and implantation, and endocannabinoids are important
for synchronizing preimplantation embryo development
with uterine receptivity for implantation. Additionally,
phospholipases also play a role in the remodeling and
the stability of lipid membranes (Robichaud et al. 2015),
therefore affecting placental and fetal development
during pregnancy. In the following, an overview of
PLA2 family members will be provided, with special
emphasis on those family members that are important
© 2016 Society for Reproduction and Fertility
ISSN 1470–1626 (paper) 1741–7899 (online)

in pregnancy, pregnancy pathologies, and (preterm)
parturition.
Classification of human PLA2 family members
Many different aspects are used to subdivide PLA2 family
members into four groups, with the most commonly found
classification being that according to Dennis (Schaloske
& Dennis 2006). This system uses cellular localization as
well as calcium dependency to distinguish PLA2 groups.
An overview of PLA2 family members is provided in
Table 1. Important structural features of each PLA2 group
are depicted in Fig. 1, whereas Fig. 2 summarizes the
action of PLA2 isozymes in maternal and fetal circulation
as well as reproductive tissues.
Secretory PLA2

Secretory PLA2s (sPLA2s) form the largest group within
the calcium-dependent PLA2 family (Murakami et  al.
2011a,b). They are typically very small enzymes
ranging between 14 and 19 kDa, with the exception
of PLA2-III (55 kDa). Apart from PLA2-XII, all group
members are closely related and share significant
sequence homology. All family members share six
absolutely conserved disulfide bonds as well as some
additional ones (Kudo & Murakami 2002), which are
specific to enzyme. In close proximity to one another,
a histidine–aspartic acid catalytic dyad and a calciumbinding loop are found in all the sPLA2s. It is also
noteworthy that many sPLA2 family members tightly
DOI: 10.1530/REP-15-0519
Online version via www.reproduction-online.org

adipocyte triglyceride lipase. NRE. EPA. PNPLA4 NRE. 1996. In addition to cytokines and hormones. sPLA2-IIA is up-regulated by pro-inflammatory cytokines. Ca2+ dependency Substrate preference (molar range) FFA released cPLA2α cPLA2β 14 14 15 14 14 16 14 14 55 19 85 110 mM mM mM mM mM mM mM mM mM mM <µM <µM AA. and Th2 cells (Balboa et al. PNPLA3 iPLA2η. EPA. LA AA. PC PS. PE. High levels of plasma sPLA2-IIA are associated with pathologies characterized by a high degree of inflammation. PAF. LA AA. PNPLA. DHA. LA AA. they are often located in cell membranes within the extracellular matrix (Murakami et al. intracellular. EPA. PNPLA9 85–88 None VI-B iPLA2γ. and major substrates are indicated. and more importantly during labor (Lappas et al. In addition to the mentioned lipases. PC Sn-1 and sn-2 position cleavage. LA AA. 2005). OA. EPA. atherosclerosis (Webb 2005). PC PS. LPC. PC Sn-1 and sn-2 position cleavage. NTE. EPA. and X but not III and XII. OA. 1998). LPA PC-TG. EPA. PE. cytosolic phospholipase A2. Qu & Lehrer 1998).reproduction-online. LA AA. neuropathy target esterase. 1996). EPA Little AA IV-C cPLAγ 60 None VI-A iPLA2β. LA AA. Thomas et al. Protein size (kDa). LA AA. OA. OA. iPLA2. such as septic shock (Pruzanski & Vadas 1991). EPA. DHA. 1998). which is constitutively expressed within various tissues and cells. calciumindependent PLA2. downregulated by glucocorticoids. LPC.R92 C Besenboeck and others Table 1 Classification of PLA2 isozymes according to Schaloske and Dennis (2006). NTE. 1996). Therefore. LA AA. DHA. Both neutrophils and macrophages are able to store the enzyme in granules and secrete it upon activation (Balsinde et  al. 2000). recently two lysosomal PLA2s (aiPLA2 and LPLA2) as well as an adipose tissue-specific PLA2 (AdPLA2) have been discovered. it is up-regulated by pro-inflammatory stimuli such as IL1. PC PC>PS+PE PC>PS Sn-1 position cleavage. rather than being secreted. OA. 1996). It is highly expressed in myocytes. patatin-like phospholipase. II. sPLA2-V sPLA2-V is another important member of the secretory phospholipase group. Ca2+ dependency. sPLA2. oxidized side chain PC-TG. 1998). PE. ATGL. PE. and additionally holds antimicrobial and anticoagulant properties (Mounier et al. likely owed to the fact that it can substitute for sPLA2-IIA activity. PNPLA2 iPLA2δ. OA. and placenta (Moses et  al. bind to heparan sulfate proteoglycans as the cationic cargo of the enzyme. PC PS+PE+PC PS+PE+PC PS. transforming growth factor-b. OA. ATGL. secretory phospholipase A2. macrophages. and respiratory distress Reproduction (2016) 151 R91–R102 syndrome (Masuda et al. PAF–AH. PE. PC Dietary TG Lysophospholipids. PNPLA6 55 155 None None NA NA NA iPLA2ε. EPA. 1996. V. DHA. Kuwata et al. sPLA2-IIA (synovial lipase) sPLA2-IIA acts as a pro-inflammatory enzyme. DHA. however. DHA. chorion–decidua. OA. LA AA. It is an 180 kDa integral www. PNPLA7 58 27 146 None None None VII-A 45 None VII-B Plasma PAF–AH.org . DHA. PLA2R forms may be produced by the action of metalloproteinases and are highly expressed in the kidney. rheumatoid arthritis (Seilhamer et  al. PLA2R1 binds sPLA2 groups I. PNPLA8 90 None NA NA iPLAζ. oxidized side chain PAF PAF Little AA No strict preference No strict preference No strict preference No strict preference Unclear NA No strict preference AA AA Acetate Acetate The official numbering system using Latin numbers as well as commonly used trivial names are given. cPLA2. PE. Similar to sPLA2-IIA. PLA2 isozymes highlighted in bold are those playing a major part in pregnancy and therefore discussed in this review. PAF. but also in immune cells such as mast cells. PC PS+PE>PC PS. DHA. PC Sn-1 and sn-2 position cleavage. and interleukin 10 (IL10. LPA Unclear Retinoic acid Lysophospholipids. LA AA. it cannot be downregulated by glucocorticoids (van der Helm et al. but also expressed in pancreas. LpPLA2 PAF–AH-II 40 None VIII-A VII-B PAF–AH 1 a1 subunit PAF–AH 1 a2 subunit 29 30 None None PLA2 subfamily Enzymes Other names sPLA2 IB IIA IIC IID IIE IIF V X III XII IV-A IV-B Pancreatic lipase Synovial lipase cPLA2 iPLA2 PAF–AH Protein size (kDa) PS. PC PS. platelet-activating factor–acetyl hydrolase. EPA. EPA. OA. amnion. 2004). neuropathy target-related esterase. receptors for sPLA2s (PLA2R) have been found to provide a regulatory mechanism for sPLA2 enzymes. OA. DHA. DHA.

Green box indicates the calcium binding domain and turquoise. The plasma and tissue concentration of PAF is determined by a balance between its biosynthesis and degradation (Arai et al. placenta. LpPLA2 Reproduction (2016) 151 R91–R102 . or trans-acetylase activity. 2013). ATGL mainly hydrolyzes dietary TG and activates TG stored in lipid droplets and white adipose tissue (Zechner et  al. In pregnancy. Augert et al. In systemic circulation. are present in both maternal and fetal circulation. the red box indicates the patatin domain with its active site serine residue being highlighted. As before. PAF–AH-II PAF–AH-II is an intracellular enzyme that shares about 41% sequence homology with the plasma form. and phospholipids (not indicated in the scheme). Although there are nine members of human PNPLAs. calcium-independent PLA2 (iPLA2) isozymes are often also referred to as patatin-like phospholipases (PNPLAs). Tsimihodimos et al. Although its precise function remains unclear. 2011). Two structurally and functionally important cysteine residues are indicated as well. which makes cPLA2 enzymes important in fertility. this enzyme attaches to LDL (80%) and HDL (20%) particles. Some PNPLAs/iPLA2s also have triglyceride (TG) lipase. 2002. consists of two intracellular isoforms (Ib and II) and one secreted isoform (plasma). Asterisks indicate amino acid residues important to active site formation. 2002). regulate cell senescence. member of this group is adipose TG lipase (ATGL). ATGL has also been shown to be expressed in human and rodent placental tissue (Barrett et al. Serum LpPLA2 levels are elevated in a number of inflammatory conditions (Vickers et al. PLA2R1 seems to serve pleiotropic effects apart from fatty acid metabolism. pro. Factors regulating PLA2 isozymes.b). The exact role of the enzyme. (D) Plasma PAF–AH. the catalytic domain. Figure 1 Schematic structure of PLA2 enzymes. (B) Cytosolic PLA2 group IVA. 1998). 2009. Platelet-activating factor–acetyl hydrolases The family of platelet-activating factor–acetyl hydrolases (PAF–AH). implantation. but also familiar to hypercholesterolemia and diabetes (Serban et al. Intracellular. 2009). 1997. Hirabayashi & Shimizu 2000). cytokines. LpPLA2 possesses a unique substrate preference for oxidized phospholipids. Orange boxes represent the seven characteristic ankyrin repeats. not all these enzymes have been assigned an abbreviation within the PLA2 classification system because most PNPLA/iPLA2 family members do not elicit classical PLA2 activity.g. esterase. The blue box indicates the catalytic site with the serine residue of the G-X-S-X-G lipase motif being highlighted. (2002).or anti-inflammatory. (A) Representative secretory PLA2 isozyme. elevated serum LpPLA2 levels have been measured in mothers suffering from pregnancy hypertension. Only the most important PLA2 isozymes and pregnancy pathologies are highlighted in this schematic overview. Plasma PAF–AH The more commonly termed lipoprotein-associated PLA2 (LpPLA2) is an extracellular enzyme produced and secreted mainly from differentiated macrophages (Tjoelker et al. preeclampsia (PE). which is the principal substrate of LpPLA2. and to be the major auto-antigen in nephropathy (Stanescu et al. (C) Calcium-independent PLA2-VIA (PNPLA9). 1995). lysophospholipase. and fetal circulation. aging. Tellis & Tselepis 2009). but no phospholipase activity at all (Murakami et  al. chemically resembling PAF. calcium-independent PLA2s Intracellular. placental membranes. This includes cell types of the uterus and trophoblasts of the placenta.org Phospholipase A2 in pregnancyR93 Figure 2 Overview of PLA2 family members in maternal circulation. green and blue boxes indicate calcium binding and catalytic domains respectively. group IIA. and gestational diabetes mellitus (GDM) – all are pregnancy-associated diseases. which degrades pro-inflammatory phospholipids (PAF). 2014) and might depend on association with either LDL or HDL (Lagos et  al. e.reproduction-online. uterine layers. 2014). 2011). The red box shows the typical short C-terminal extension. The most important www. Cytosolic PLA2s The cytosolic PLA2 (cPLA2) subfamily consists of three isozymes that are expressed in the cytosol of most cell types ubiquitously and constitutively (Leslie 1997. membrane receptor with a very large extracellular and a very small intracellular domain. 2002). 2002. chemokines. 2011a. The activity of cPLA2 and sPLA2 enzymes seems to be interconnected (Murakami et al. 2009). Song et  al. Silva et al. remains enigmatic (Marathe et al. ovulation. Modified scheme from Murakami et al. and placentation (Uozomi et al. and cancer (Lambeau 1999. binding of sPLA2 to its receptor participates in both positive and negative regulation of sPLA2 functions as well as clearance of sPLA2.

serum sPLA2-IIA levels were lowest in the luteal phase and comparably high in the menstrual and follicular phases. other studies contradicted these findings (Tempfer et al. and phospholipid metabolism is certainly activated both in preterm labor and in apparent inflammatory diseases (Koyama et al. Within this subgroup. and fetal membranes express high amounts of sPLA2-IIA. among the three trimesters. the released AA converts to lipid mediators by COXs (COX1 and COX2). In addition. no further changes in serum sPLA2-IIA levels were observed. In total. making up for about 80% of total sPLA2 activity. hetero-trimeric enzyme with substrate preference for PAF. Appropriate control groups were not indicated in all the mentioned www. IL8.org . and IL6 levels were significantly elevated in the sera of women with amnionitis compared with those delivering preterm without infection or the control group. these observations suggest that sPLA2-IIA concentration may be a useful indicator for preterm labor. as well as in pregnant women throughout the pregnancy. Therefore. This is corroborated by increased activity of PLA2 during late gestation. which is catalyzed by the action of both secretory and cPLA2 family members. oxytocin mRNA increases at term. is sPLA2-IIA (synovial phospholipase). PAF–AH-Ib PAF–AH-Ib is an intracellular. to allow parturition. however. serum PLA2-IIA concentrations were significantly higher in postpartum women than in normal pregnant women. 1997). 2000). several uterine tissues. no further known association with pregnancy has been described so far (Hattori et al. (1993) that clearly showed low levels of sPLA2-IIA during the first trimester. 2006). this did not reach statistical significance. supporting the idea that it may act as a local mediator rather than a circulating hormone.reproduction-online. likely to allow for proper implantation. Despite the progress in this field. A study on 38 women delivering preterm showed that their serum sPLA2-IIA concentration and activity were significantly higher than those in a control group delivering at term. 1993. PLA2 levels at term and in preterm labor The induction of parturition is dependent on three rate-limiting steps: first. but also in pregnancy. There was also no significant difference for circulating PLA2-IIA levels between maternal and fetal serum. Conclusions drawn from studies on PE have to be interpreted carefully as children from PE pregnancies are often delivered pre-maturely and control groups would have to be matched for gestational age. not only sPLA2-IIA concentration but also total PLA2 activity was assessed. It exerts a substrate preference similar to LpPLA2 but acts intracellularly with not only hydrolase but also trans-acetylase activity. sPLA2-IIA was also extensively investigated in the serum of preterm labored women. 19 women were suffering from chorioamnionitis. PLA2 levels in the first trimester Hayashi et al. and that sPLA2 is in turn induced significantly during labor. which could be likely due to the impact of hormones such as estrogen. however. Also.b). Oxytocin is another potential factor that could be contributing to modulating PLA2 levels. In this study. Secondly. Although the cellular origin of sPLA2-IIA seems to be still unknown. specific PG synthases produce PGs. 2001). this study contradicted the work of Pulkinnen et al. and Lefebvre et  al. Serum concentration and activity correlated significantly. (1992) showed that during gestation.R94 C Besenboeck and others (Matsuzawa et al. sPLA2IIA concentration and activity were even higher compared with the general preterm group. which is needed for the onset of labor from these precursors. serum sPLA2-IIA levels were about twice as high as in the menstrual and follicular phases. but not oxidized phospholipids. recently two lysosomal PLA2s (aiPLA2 and LPLA2) as well as an adipose tissue-specific PLA2 (AdPLA2) have been discovered but are not yet extensively studied (Murakami et al. which is elevated during pregnancy. In pregnant women. which can be explained by sPLA2-IIA. Also inflammatory markers such as CRP. PLA2 levels in PE and GDM Increased serum levels of sPLA2-IIA have been reported in pregnant women suffering from both mild and severe PE (Pulkkinen et  al. These results Reproduction (2016) 151 R91–R102 suggest that a regulatory mechanism of PLA2-IIA may exist during the normal menstrual cycle and at puerperium. an infection associated with severe inflammation. the lack of identification of the mechanisms of human parturition has limited the specific and effective diagnosis and treatment of preterm labor and subsequent birth. 1994). High levels of intracellular PAF–AH-II activity have been detected in placental trophoblast cells. the release of AA. and in the last step. 1995). In non-pregnant women. However. 2011a. interestingly. Lim et  al. however. The tissue-specific enzyme distinctly reveals the importance in the development of fetal brain and spinal cord. Within the preterm group. in pregnant women. (2000) investigated serum sPLA2-IIA levels in non-pregnant women during their menstrual cycle. It is the most potent uterotonic agent known so far. suggesting its possible relationship with labor induction (Gu et al. the placenta. apart from that. Serum PLA2 levels in pregnancy The best investigated PLA2 family member in general. however.

LpPLA2 (plasma PAF–AH) has emerged as a biomarker for cardiovascular risk (Castro FariaNeto et al. term/in labor. However. The main outcome of this study was a significant increase in sPLA2-IIA in amnion and decidua in the preterm compared with the term group. Some pregnancies are therefore affected by conditions such as GDM. In this study. and metabolic syndrome (MetS). which are considered transient and disappear after delivery. Furthermore. 20% had signs of MetS. 2004) and has extensively been studied in atherosclerosis. sPLA2-IIA expression in placental tissue and chorion–decidua was the highest. and blood pressure were higher in women with a history of PE than in controls. Throughout the course of pregnancy. cPLA2-IV mRNA was expressed in all the three tissue types at similar levels (Johansen et al. studies. this was not true for all women and some still had increasing LpPLA2 levels over the second and third trimesters. or hypertension.reproduction-online. whose LpPLA2 levels were measured in the first. whereas cPLA2-IV levels remained constant. and cPLA2-IV. However. LpPLA2 mass was correlated with the development of postpartum hypertension (systolic blood pressure) as well as LDL-C levels (Zhou et al. So far. 43% who had high levels of LpPLA2 in the second trimester also developed PIH. although infection is often associated with preterm labor. PLA2 action within the placenta is not only important in parturition (Lappas et al. their role in homeostasis and pathophysiology during pregnancy has not been clearly established. and placenta samples were assayed for both sPLA2-IIA concentration and total PLA2 activity. Another study that investigated LpPLA2 in pregnancy hypertension was conducted prospectively in 51 pregnant women. sPLA2-V. different placental cell types. Another study investigating LpPLA2 levels in women with a history of GDM showed that LpPLA2 levels in maternal serum remained significantly higher compared with control women for up to 2 years after delivery. one can speculate that sPLA2-IIA plays a more important role in inducing myometrial contractions and labor onset than cPLA2-IV. (2001) using preterm and term groups with subgroups being in labor or without previous labor. 2014). Three recent studies investigated LpPLA2 levels in postpartum women. In this context. Derbent et al. BMI. Within the case group. 2000). mothers adapt to a lot of metabolic challenges such as insulin resistance. but undetectable in decidual tissue. amnionitis was not characterized by increased levels of sPLA2-IIA in decidua. myometrial samples were collected from four different groups: a term/no labor. The general observation among the study population was that LpPLA2 levels were higher in the first than in the second and third trimesters. Although PLA2 isozymes have been extensively studied within uterine tissues. Furthermore. knowing the relationship between sPLA2-IIA and inflammation. which is the actual contractile layer within the uterine wall.org Phospholipase A2 in pregnancyR95 PLA2 in the human placenta AA mobilization by PLA2 and subsequent PG synthesis is thought to be a pivotal event in the onset and/or maintenance of human labor. and 5% became hypertensive (Mai et al. 1999). Of the total women. investigated LpPLA2 levels in women with a history of GDM with respect to their future risk of developing MetS. whereas only 8% of women who had low levels of LpPLA2 in the second trimester developed PIH. but undetectable in amnion. ten women developed pregnancyinduced hypertension (PIH) later in the third trimester. hyperlipidemia. Interestingly. and fetal membranes. amnion. 1997). and a preterm/in labor group. preterm/no labor. three PLA2 isozymes have been shown to be especially important for placental AA release and onset of parturition: sPLA2-IIA. 50% of women showed signs of MetS and 25% were diagnosed with type 2 diabetes mellitus (T2DM). Both in the preterm and in the term groups. Therefore. In this study. A study focusing on sPLA2-IIA and cPLA2-IV in the human myometrium (Slater et  al. investigated PLA2 function and its association with labor and onset at term and preterm deliveries. although the mRNA expression levels of these enzymes within the tissue appears to be diverse. and third trimester of pregnancy (Okumura et al. Zhou et al. cholestasis. second. or placenta compared with Reproduction (2016) 151 R91–R102 . spontaneous onset of labor significantly induced sPLA2IIA expression in the myometrium. found that LpPLA2 levels as well as LDL-C. in a subset of women in this study. 2004) but also for catabolism and transport of TG from the mother to the fetus across the placenta (Freed et al. This is the first study which found that women – who had delivered up to 5 years before the study was conducted – still presented with significantly lower HDL levels but higher insulin resistance index. The authors therefore suggested LpPLA2 levels along the course of pregnancy as one potential risk marker for PIH. as PE is characterized as a highly inflammatory condition. 2011). amnion. www. sPLA2-V mRNA was highly expressed in the placenta and amnion. Of these. Decidua. Placental PLA2 in term and preterm labor sPLA2-IIA and its role in preterm labor was also investigated by Lappas et al. In the last few years. 2014). and possibly hypertension. hyperlipidemia. diabetes. and most importantly higher serum LpPLA2 levels compared with controls (Derbent et  al. there is an increased risk for cardiovascular disease in these mothers later in their lives. 2014). TG. Nevertheless. increases in sPLA2-IIA appear probable. 10% of women who had GDM later developed T2DM. increased levels of sPLA2-IIA in amnion in the preterm group were associated with premature rupture of membranes. The placenta as the connective organ between mother and fetus acts as the separating barrier between the maternal and fetal circulations and ensures nutrient and oxygen supply from the mother to the growing infant.

Levels were generally higher in chorion–decidua than in placenta.. our research group compared the mRNA levels of various PLA2 family members in four distinct primary cell types of the human placenta. increased ATGL and CGI-58 could point toward increased lipolysis in GDM placentae. Immune histochemistry showed the presence of ATGL in placental stromal cells (e. which is frequently observed in neonates born from diabetic pregnancies (Herrera & Ortega-Senovilla 2010. sPLA2IID mRNA was shown to be expressed in a very low amount in human myometrium.reproduction-online. this did not translate to enhanced ATGL protein abundancy in GDM placentae. A study on PE placentae showed that both the levels of PAF. and PLA2G7 (encoding LpPLA2) in SCT. M-type receptor for sPLA2s (PLA2R1) has been detected in human placenta (Moses et  al. ATGL (PNPLA2) mRNA. 2010). sPLA2-VI. In vitro. 1999). Comparing the mean expression intensity. as well as mRNA of its co-activator CGI-58. were up-regulated in GDM placentae. which is able to degrade PAF. sPLA2-V. did not find any significant changes in sPLA2-IIA neither between preterm and term groups nor between labor and non-labor groups (Munns et al. most members showed differential expression with an average of 1. Table 3).R96 C Besenboeck and others controls. Within the decidual layer. they investigated the effect of TNFα and leptin on sPLA2-IIA and sPLA2-V and found that the expression of these PLA2 isozymes was induced. PAF–AH-II is additionally expressed in placental trophoblast cells. they likely represent a link between inflammation and lipid metabolism. and LpPLA2 mRNA was increased up to three-fold. mRNA levels are related to protein levels. Also the cytosolic PAF–AH isoforms I and II have been shown to be expressed in pregnant and non-pregnant myometrium (Yasuda & Okumura 2001). Also. tumor necrosis factor alpha (TNFα) and leptin mRNA were increased in obese placentae. To the best of our knowledge. Placental PLA2 in pregnancy-related pathologies The only iPLA2 member shown to play a role in placental tissue so far is iPLA2ζ. when comparing the expression of PLA2 members between placental endothelium (combined AEC and VEC expression intensities) and trophoblast (combined CT and SCT expression intensities). it is likely that www. Lawlor et al.82-fold. arterial endothelial cells (AEC). the only study investigating PLA2 family members in the placenta focusing on lipid catabolism between the  mother and the fetus was conducted by Varastehpour et  al. On contrary. were higher compared with controls (Gu et  al. a cPLA2) showed differential expression between AEC and VEC with a 1. Newborns of diabetic or obese mothers are often considerably bigger and have higher amounts of body fat than children born to normoglycemic or lean mothers (Durnwald et al. Glucose intolerance and alterations in lipid metabolism are common features of pregnancy. sPLA2-IID mRNA and protein was lower in the labor group. Barrett et  al. A similarly designed study. and endothelial layer of placental vessels. The authors suggested that sPLA2-IID may not be important in labor onset but serves an important role in placental immune function and tolerance of the fetus as sPLA2-IID has been shown to be an effector for regulatory T-cells (Tregs). However. (2014) showed the presence of ATGL in placental tissue for the first time. but not in the amnion. They investigated PLA2 mRNA levels in the placenta of normal and obese newborns and found that sPLA2-IIA. however. and interestingly. (2013). Mosher et al. whereas expression of PLA2 members in CT and SCT was similar (Table 3). in uterine tissue.71-fold.org . 2004). They concluded that increased sPLA2 action in the placenta of obese neonates may result in even more FFAs available for fetal adipogenesis but also for generation of pro-inflammatory mediators. PLA2R1 was found to be expressed in chorion–decidua and placental tissue. more commonly known as ATGL (PNPLA2). Induction of PAF–AH-II was suggested to be a compensatory Reproduction (2016) 151 R91–R102 mechanism to clear PAF and therefore to decrease the inflammatory component of PE. fetuses would receive more TG. but by far highest in decidua. This reflects that the metabolic status of the mother affects the offspring’s outcome already in utero. 2009). and trophoblast PAF–AH-II. all studies on PLA2 in the placenta and their principal results are summarized in Table 2. placenta. If so. As the action of PLA2s also gives rise to pro-inflammatory lipid mediators. As the expression of PLA2R1 did not differ between endothelium and trophoblast (Table 4). which explains the higher fetal fat mass accretion in late pregnancy. Hofbauer cells (HBCs)). cytotrophoblasts (CT). a potent mediator of inflammation. PLA2G16 (encoding an AdPLA2) in CT. was uniformly expressed in all placental cell types. 2006). 1998) and could represent an additional mechanism regulating sPLA2 activity within this tissue. PLA2G15 (encoding a lysosomal PLA2) was mostly expressed in AEC and VEC. only PLA2G4F (encoding PLA2-IV-F. PLA2 expression in placental cell types Using gene expression analysis. however. Also this study compared groups at term with and without labor. and amnion. Considering fold-change values. M-type PLA2 receptor. placental expression increased with labor onset. sPLA2-IID. syncytiotrophoblast (SCT). (2014) investigated another PLA2 family member. This may lead to macrosomia. and SCT (data analyzed from Cvitic et  al. (2006). Nevertheless. PLA2R1. Tregs have been shown to be important for proper implantation without rejecting the fetus (Jin et al. For a better overview. venous endothelial cells (VEC).g.

Additionally. Farrugia et al. IHC. Munns et al. PLA2-IVa. RT-qPCR and tissue RNA WB and protein sPLA2-IIA and sPLA2-V. western blot. the enzyme was increased if the fetus was to be delivered prematurely (Pulkkinen et  al. Pulkinnen et al. PLA2-IID. PLA2-X. and PLA2-IB sPLA2-IID X X Non-labor vs labor* X NI X References Explant culture Activity assay. sample types and detection techniques used are indicated. WB. this is caused by sPLA2-IB present in meconium itself. uterine tissue. which is a common phenomenon in preterm infants. PLA2-IVc. On the one hand. RT-quantitative real-time PCR. amnion cPLA2-IV and sPLA2-V. ELISA (1997) Tissue homogenate ELISA Lappas et al. PLA2-XII. obese groups* PLA2-IIE. and PLA2-IVb. investigation of pulmonary lavage fluids showed that local production of sPLA2-IIA is also contributing to inflammation in MAS (De Luca et al. which is responsible for the degradation of surfactant and therefore harmful to the neonate’s lung development. not investigated. PLA2-IIF. (1997) RNA. cPLA2-IV PLA2-VI. On the other hand. PLA2-VII. ELISA (1999) PLA2 unspecified X NI NI sPLA2-IIA X Preterm/term – NI labor/no labor groups X X NI sPLA2-IIA and cPLA2-IV X X X sPLA2-IIA and cPLA2-IV X X X sPLA2 activity was highest in amnion during labor Correlation of secreted and intracellular PLA2 protein More sPLA2-IIA was present in preterm tissues than term All three expressed in placenta. WB. apart www. PLA2s are not regulated by the respective receptor in these two placental compartments. Phospholipase A2 in pregnancyR97 Table 2 Overview of important PLA2 family members in human placental tissue and fetal membranes. Tissues/fetal membranes PLA2 isozyme Placenta Chorion–decidua Amnion Results Sample type Detection technique sPLA2-IIA X X X Tissue homogenate Activity assay. PLA2-IIA. IL1binduced sPLA2-IID dose dependently Decidual cells. high levels of cPLA2 in amnion cPLA2-IV was highest in amnion. (2014) The expression of PLA2 isozymes in the placenta and fetal membranes is marked with an X. 24 children with proven sepsis. (2006) Mosher et al. RT-qPCR. For better understanding of different results from different studies. 1990). NB. in eight out of 14 cases.reproduction-online.to ten-fold the concentration of synovial-type PLA2. Enzyme activity was highest in the septic children and was also significantly elevated Reproduction (2016) 151 R91–R102 . and fetal membranes. leptin was shown to regulate these two PLA2s sPLA2-IID mRNA was highest in decidua in the non-labor group and amnion of the labor group. sPLA2-IIA was highest in placenta sPLA2-IIA and sPLA2-V were higher in obese placenta. Moreover. pregnancy-induced hypertensive diseases increased by four. immunohistochemistry. (2001) RNA RT-qPCR Johansen et al. sPLA2-IIA levels are well established in the serum of newborns suffering from sepsis. However. PLA2 in neonates Although PLA2 family members are well investigated in maternal circulation and even more comprehensively in placentae of different hosts. 2011). and IHC (2004) Isolated cells and RNA RT-qPCR Varastehpour et al. Neonates suffering from meconium aspiration syndrome (MAS) develop respiratory distress. no other parameters of neonatal distress or inflammatory markers were investigated. very little is known about PLA2 levels. activity. (2000) RNA NB Freed et al. and 55 proven healthy children were investigated for their sPLA2-IIA activity. In a study on newborns admitted to ICU. X Control and NI PLA2-V. northern blot. chorion sPLA2-IIA and cPLA2-IV High amounts of sPLA2-IIA in placenta. protein and tissue sections RT-qPCR. investigated sPLA2-IB and -II (pancreatic and synovial phospholipase) levels in umbilical cord blood and found that high levels of sPLA2-IB in cord blood were reflected by poor Apgar scores in these neonates. Slater et al. and function in the neonatal circulation. NI.org from Apgar score and premature delivery. 77 children with suspected infection.

8 ± 0.06 0.R98 C Besenboeck and others Table 3 Expression of PLA2 family members in various cell types of human term placenta. fold-change was calculated as the ratio of mean expression for endothelium vs trophoblast. Data were used from Cvitic et al.1 8. 6 ± 0.7 ± 0.98 0.1 6. syncytiotrophoblast. cytotrophoblast.5 6.001 <0.6 7.1 6.05 <0. arterial endothelial cells.7 ± 1.98 0.01 <0.2 4.0 3.74 1. 2008).7 ± 0.1 ± 0. AEC.5 5.2 5.2 6.80 1.0 3.00 ± 0.98 0.4 ± 0.1 6.0 ± 0.1 6.95 1.4 4.98 1.1 ± 0.7 ± 0. However.001 <0.11 0.1 ± 0.01 <0.1 6.8 4.05 NS NS NS NS NS Values represent mean mRNA expression intensities from endothelium (n = 18) and trophoblast (n = 20) measured by Affymetrix GeneChip Human 1. Moreover.1 ± 0.2 ± 0. in the ‘suspected infection’ group compared with controls (Schrama et al.8 ± 0.4 8.9 ± 0.3 ± 0.7 6.4 ± 0.94 1.9 ± 0. The authors suggested that this is not only due to high sPLA2 in serum but also locally high levels of sPLA2 in neonatal lungs.1 6.77 0.8 ± 0.3 ± 0. VEC.2 8.5 ± 0.0 ± 0.4 ± 0.05 NS NS <0.3 ± 0.3 ± 0. this study showed that the neonates from women with severe PE have higher plasma PAF–AH activities.3 ± 0.0 ± 0.97 0.6 ± 0. Reproduction (2016) 151 R91–R102 www.001 <0.86 0.9 ± 0.5 ± 0.1 8.1 4.1 6.02 0.1 6. FC. LDL levels were significantly higher than in control neonates.9 ± 0.6 ± 0.0 ST arrays.001 <0.2 ± 0.2 8.5 3. in offsprings born to PE pregnancies.001 <0.01 NS CT SCT 10.0 ± 1.1 6.8 ± 0.99 1. FC.1 7.05 NS <0.0 ± 0.5 ± 0.2 4.3 6.0 ± 0.4 10.1 8.98 1.2 3.10 0.99 0.1 6.7 ± 0.99 1.1 7.01 <0.4 ± 0.00 0.73 1.5 FC 0.8 ± 0.8 ± 0.1 6.1 8.5 ± 0. In summary. Data were used from Cvitic et al.3 ± 0.2 6.4 ± 0.5 ± 0.3 ± 0.6 ± 0.9 ± 0.80 1. sPLA2 activity correlated positively with other markers of inflammation.2 ± 0. and SCT (n = 10) measured by Affymetrix GeneChip Human 1.2 6.2 8.1 5.3 8.9 ± 0. and higher TG:HDL-C ratio than the neonates from women with normal pregnancies. such as CRP and IL6 levels as well as leukocyte count.3 3.6 ± 0.3 10.0 ± 0.72 1.9 ± 0.1 4.4 8. SCT.2 ± 0.00 0. Expression intensities range from 1 to 13.05 NS NS NS <0.6 ± 0.5 ± 0.3 ± 0.1 4.1 4.7 4. VEC (n = 9).1 6.01 NS NS <0.1 8.7 ± 0.4 8.7 4.1 7.4 ± 0.69 1.9 ± 0.4 ± 0.1 7.2 7.1 6.2 5. Also LpPLA2 activity was higher in cord blood in the PE group and activity was elevated in LDL particles compared with controls.6 ± 0.3 5.4 6.95 0.1 8.01 <0.0 ± 0.1 6.1 8.01 <0.6 ± 0. venous endothelial cells.2 9.9 ± 0.1 3. Expression intensities range from 1 to 13.2 6.05 1.00 0.9 ± 0.001 <0.98 1.4 7.5 ± 0.1 ± 0.88 1.1 7. 2012).6 ± 0.7 ± 0.8 ± 0.71 1.98 0.2 6.001 <0.2 8.1 4.2 6.2 ± 0.2 3.1 6. A study investigating LpPLA2 (plasma PAF–AH) activity and distribution among LDL and HDL particles within both maternal serum and neonatal cord blood in PE pregnancies showed that there was no significant alteration in LpPLA2 activity and distribution in maternal blood caused by PE (Fan et  al.1 8.3 5.5 3.3 3.8 ± 2.81 1.80 1.2 6. fold-change was calculated as the ratio of mean expression for AEC vs VEC and CT vs SCT respectively. sPLA2-IIA levels were especially high in children experiencing respiratory distress syndrome in addition to sepsis.7 ± 0.5 ± 0.8 ± 0.3 6.1 5.6 ± 0.05 0.5 ± 0.2 6.2 3.5 8.4 6.1 ± 0.1 5.72 1.05 NS NS NS NS NS NS NS <0.98 0.10 P value (AEC vs VEC) NS NS <0.0 8.5 ± 0. Results suggest that the neonates of the patients might present a chronic inflammation Table 4 Expression of PLA2 family members in endothelium and trophoblast of human term placenta.5 ± 0.9 ± 0.2 10.91 1.07 1.3 8.9 ± 0.1 ± 0.2 ± 0.7 ± 0.1 5.8 ± 0.97 0.02 0.97 0.82 1.001 <0.4 6. sPLA2-IIA is already a valid marker of sepsis.1 6.9 ± 0.4 ± 0.org .3 ± 0.4 7.0 ± 0.4 ± 0.5 1.0 ST arrays. Gene symbol PLA2G7 PLA2G15 PLA2G6 PLA2G16 PAFAH2 PLA2G12A PLA2G2D PLA2G10 PLA2G4D PLA2G3 PLA2G2A PLA2G4F PLA2G4A PLA2G5 PLA2G1B PLA2G4E PLA2G2E PLA2R1 Endothelium Trophoblast FC (endothelium vs trophoblast) P value (endothelium vs trophoblast) 5.1 8.01 NS NS NS NS NS <0.7 ± 0.2 ± 0.1 8.95 0. causing hydrolysis of lung surfactant phospholipids.74 1.1 7.77 1.2 6.9 ± 0.8 ± 0.9 ± 0.8 1.99 1.01 <0.1 5. CT (n = 10).6 9.01 Values represent mean mRNA expression intensities from AEC (n = 9).7 ± 0.70 1.3 ± 0.3 6. In adults.1 ± 0.72 1.5 6.1 4. CT.96 1.3 ± 0.7 ± 0.3 6. (2013).4 ± 0.3 ± 0.5 ± 0. higher ratio of LDL–PAF–AH to HDL–PAF–AH activities. (2013).01 <0.99 1.6 ± 0. Gene symbol PLA2G7 PLA2G15 PLA2G6 PLA2G16 PAFAH2 PLA2G12A PLA2G2D PLA2G10 PLA2G4D PLA2G3 PLA2G2A PLA2G4F PLA2G4A PLA2G5 PLA2G1B PLA2G4E PLA2G2E PLA2R1 AEC VEC FC 5.3 9.01 NS <0.2 9.08 P value (CT vs SCT) <0.reproduction-online.

(1993) NA Okamura et al. most inhibitors of PLA2 activity act rather unspecific on various PLA2 isozymes (Yedgar et  al. J Loegl. most pregnancy pathologies are characterized by similar metabolic changes such as elevation of certain cytokines. Abbreviations: ↑. an accumulation of placental macrophages (so-called HBCs) has also been reported in GDM and PE pregnancies (Evsen et al. U Lang. GDM (and/or obesity). IL6. 1996. and PE. insulin resistance is augmented. 2013). obesity. so far it is more common to reduce PG and leukotriene production in certain inflammatory conditions. elevated levels of certain pro-inflammatory cytokines have been reported. respectively. to Schrama et al. inflammation of the placenta without a detectable infectious agent). status. is given if only maternal or neonatal outcome. In GDM. increased. (2008) CRP. e. Therefore. IL1b. Modulation of PLA2 activity could therefore be a strategy to treat preterm labor onset. IL1. However.g. PLA2s seem to be of tremendous importance throughout various stages of pregnancy as well as in a number of common pregnancy pathologies (as summarized in Table 5). 2014). www. Kuwata et al. macrophages. Faas et  al. 2006. (1993) Lim et al. and leukocyte count Results on maternal and neonatal outcome with respect to serum PLA2 isozyme levels are summarized and compared. Yu et al.g. and/or increased oxidative stress. 1998). no correlation with cholic acid levels Elevated serum LpPLA2 levels in second trimester appeared to serve as risk marker for PIH later in third trimester NA Derbent et al. M Peinhaupt. IL6. and IL10 are able to regulate sPLA2-IIA and sPLA2-V (van der Helm et al. inhibitors of sPLA2-IIA often also inhibit the closely related enzymes sPLA2-V and sPLA2-X. Pathology PLA2 isozyme Maternal outcome Neonatal outcome References Preterm delivery sPLA2-IIA Severe preeclampsia sPLA2-IIA sPLA2-IIA sPLA2-IIA LpPLA2 ↑ Serum levels ↑ Serum levels ↑ Serum levels Serum levels unchanged Serum levels unchanged. adverse lipid profile Pulkinnen et al. Reproduction (2016) 151 R91–R102 . or placental inflammation.. 2007). insulin resistance. Conclusion In general. Enhanced activity of these secretory enzymes could contribute to some of the observed symptoms of these conditions: e. or infiltration of immune cells into the placenta. S Kopp. 2012. Insulin resistance is a necessary metabolic alteration in pregnancy to ensure energy supply of the fetus and to maintain a glucose gradient across the placenta. and low HDL-C levels in many studies (Derbent et al. and also Tregs. smaller proatherogenic LDL particles. Katzman 2015). in GDM. For instance. preterm labor in PE or macrosomia of the fetus by enhanced lipid catabolism in GDM and obesity. These three conditions have also been characterized by poor maternal lipid profiles. (2012) Gestational diabetes LpPLA2 NA NA NA NA ↑ Serum levels adverse lipid profile NA ↑ Serum levels Women developed T2DM. Raghupathy 2013. (1995) Tempfer et al. Mai et  al. However. (2014) NA C Besenboeck. however. 2011. G Desoye and C Wadsack (unpublished observation) Pulkinnen et al. derailed lipid metabolism.org Inflammation and presence of pro-inflammatory cytokines also play an important role in other pregnancy conditions. e. 2014). PE. NA. anti-inflammatory IL10 was shown to be down-regulated in these conditions (Gomes et al. chorioamnionitis (an infectious disease of the placenta) and villitis of unknown etiology (VUE.g. MetS. TNFα. 2013. MetS after pregnancy NA ↑ Plasma levels LpPLA2 LpPLA2 Cholestasis sPLA2-IIA Pregnancy-induced hypertension (PIH) LpPLA2 Sepsis sPLA2-IIA Serum levels unchanged. not applicable. Upward facing arrows indicate elevations of the respective isozyme within serum. (1999) ↑ Serum levels Corr. (2001) Fang et al. high LDL-C. Tamblyn et  al. enhance the secretion of sPLA2s and may therefore cause alterations in PLA2 activity and changes in lipid metabolism within placental tissue. 2009). These macrophages. Also. e. (2011) Mai et al. was investigated. MetS after pregnancy ↑ Serum levels NA Women developed T2DM. metabolic syndrome. in addition to an unfavorable lipid profile. IL2. Phospholipase A2 in pregnancyR99 Table 5 PLA2s in pregnancy pathologies and maternal and fetal outcome. 2013. treatment opportunities so far are limited: fine-tuned modulation of only certain PLA2s would be necessary. 2013. (1993) Pulkinnen et al. Moreover.reproduction-online. Fan et  al.g. T2DM. and IL6. and it is also often observed in obese pregnant women as well as women suffering from PE (Rademacher et  al. type 2 diabetes mellitus. especially if exposed to pro-inflammatory mediators. Both conditions have been characterized by massive infiltration of placental tissue with T-lymphocytes. Garcia-Garcia et  al. with high TG. TNFα.

Rice G. 2003).271.08.1074/ jbc. However. Koizumi  H. Hirabayashi T & Shimizu T 2000 Localization and regulation of cytosolic phospholipase A 2. which can be passed by nanoparticles (Grafmüller et al. Arai H & Inoue K 1994 Miller-Dieker lissencephaly gene encodes a subunit of brain platelet-activitng factor. Alexandre SM. Huston-Presley  L. 2011). Cvitic  S. Zhang T. Adachi H. Journal of Endocrinology 153 151–157. Journal of Biochemistry 131 635–640. Biochimica et Biophysica Acta 1488 124–138. American Journal of Obstetrics and Gynecology 191 804–808. Conti G. Ozler  A. FWF. Wong M. Aoki  J & Inoue  K 2002 Platelet-activating factor acetylhydrolase(PAF–AH). Winstead MV. S Cvitic has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013).2013.87) Farrugia W.jbchem. Pediatric Research 72 426–431.033) Evsen  M. Gras  B. Kubala  MH. (doi:10. Simavli  S. within the DK-MOLIN program (W1241).1074/jbc. Future studies will hopefully help in gaining this knowledge and improve health care for mother and child. These techniques could also be used in order to overcome the placental barrier. Baran  O. Gu  Y. Simonnet H et al.1016/j. Ed Colombo GI. Funding C Besenboeck is funded by a training grant of the Austrian Science Fund. Sevgili  S. Liu  X-H. Krug  HF. Guo P-F & Li D-J 2009 The CD4+CD25 bright regulatory T cells and CTLA-4 expression in peripheral and decidual www. Carnielli VP & Capoluongo E 2011 Role of distinct phospholipases A2 and their modulators in meconium aspiration syndrome in human neonates. Scott K & Brennecke S 1997 Release of Type II phospholipase A2 immunoreactivity and phospholipase A2 enzymatic activity from human placenta.ajog. passing the placental barrier and treating placental inflammation without affecting the fetus is challenging. de Launoit Y. Placenta 27 744– 749. He  G-L. 2013 PLA2R1 kills cancer cells by inducing mitochondrial stress. Herrera E & Ortega-Senovilla H 2010 Disturbances in lipid metabolism in diabetic pregnancy–are these the cause of the problem? Best Practice & Research: Clinical Endocrinology & Metabolism 24 515–525.2010.1007/ s00134-011-2243-z) Derbent  A. Journal of Biological Chemistry 271 32381–32384. Frontiers in Immunology 5 298.1371/journal. (doi:10. Prescott SM & Zimmerman GA 2005 Regulating inflammation through the anti-inflammatory plateletactivating factor acetyl hydrolase. Woodruff  TM. Freed K & Moses E 1997 Differential expression of type II.1371/journal. Zhu et al. Amini  S & Catalano  P 2004 Evaluation of body composition of large-for-gestational-age infants of women with gestational diabetes mellitus compared with women with normal glucose tolerance levels. PLoS ONE 9 e104826.1097/ MOL.pone. Tsujimoto M. (doi:10. Intensive Care Medicine 37 1158–1165. Kargili  A. 2011. Furthermore.0104826) Castro Faria Neto H. Tischfield JA & Dennis EA 1996 Novel group V phospholipase A 2 involved in arachidonicacid mobilization in murine P388D 1 macrophages *more recently described groups IIC and V.3109/09513590.1016/S1388-1981(00)00115-3) Jin L-P. Le Calvé  B. Denny  KJ. O’Donoghue 2014). Balsinde J. Gynecological Endocrinology 27 128– 133. in order to develop better treatment strategies. Gümüs  I.2003. American Journal of Reproductive Immunology 69 545–557. Free Radical Biology and Medicine 65 969–977. deeper understanding of the relationships between inflammation and lipases and lipid metabolism in the placenta. Journal of Visualized Experiments 18 e50401. Chen Q-Y. Nature 370 216–217. IV and cytosolic PLA2 messenger RNA in human intrauterine tissues at term. by blocking COX and LOX pathways than by blocking sPLA2.11. Sak  M. (doi:10. translating results from mouse models into humans is problematical: Varespladib and Darapladib compounds inhibiting sPLA2-IIA and LpPLA2.pone. Spaans  F & De Vos  P 2014 Monocytes and macrophages in pregnancy and pre-eclampsia. Desoye  G  & Hiden U 2013 The human placental sexomediffers between trophoblastepithelium and villous vessel endothelium. methods to regulate sPLA2 action via site-directed delivery of small peptide molecules on nanoparticles and liposomes are being developed and show promising results (van den Hoven 2011. Analytical and Quantitative Cytopathology and Histopathology 35 183–188. (doi:10. showed promising effects in the treatment of atherosclerosis and vascular disease in mice. Memórias do InstitutoOswaldo Cruz 100 83–91. Zhang  J-X & Bai  H 2012 Maternal and fetal plasma platelet-activating factor acetylhydrolase activity and distribution in pre-eclampsia. Minucci A.50. In addition. Currently. Piastra M. is still needed. Torloni MR.2012. (doi:10. Pietrini D.1016/j. 2015). Hackl  H.a003145) Augert  A. Nelson  MD. Scholz Romero K. Koca  C. Hattori M.org .487612) Durnwald  C.6758) Reproduction (2016) 151 R91–R102 Barrett  HL. (doi:10. Molecular Human Reproduction 3 493–499. Journal of Biological Chemistry 271 6758–6765. Stafforini DM. Deveci  E. Zhang  S. Endo  S & Hata  T 2000 Serum group II phospholipase A2 levels during menstrual cycle and pregnancy. Ferrand  M. but also maternal and fetal circulation.R100 C Besenboeck and others sepsis. but not in man. Manser  P. Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Kalkanli  S. (doi:10. Tripodi D. Girard  CA.32381) Balsinde J & Dennis E 1996 Distinct roles in signal transduction for each of the phospholipase A enzymes present in P388D macrophages. liver toxicity is observed when blocking COX and LOX pathways. Fan  P.271. project Early Nutrition under grant agreement number 289346. Faas  MM. Gueuvoghlanian-Silva BY.reproduction-online. Nevertheless. Bouchet BP. respectively. Current Opinion in Lipidology 20 327–332. (doi:10. Grafmüller  S. Lopalco et al. (doi:10. PLoS ONE 8e 79233. Zuppi C. Vindrieux  D. Erdem E & Seker U 2013 Human placental macrophages (Hofbauer cells) in severe preeclampsia complicated by HELLP syndrome: immunohistochemistry of chorionic villi.1093/oxfordjournals. blocking sPLA2 would probably have fewer side effects (Martel-Pelletier et al. Wick  P & von  Mandach  U 2013 Determination of the transport rate of xenobiotics and nanomaterials across the placenta using the ex vivo human placental perfusion model. Longtine  MS. Gynecologic and Obstetric Investigation 50 123–126. Burlison  SA & Wang  Y 2006 PAF levels and PAF–AH activities in placentas from normal and preeclamptic pregnancies. Garcia-Garcia  H & Serruy  P 2009 Phospholipase A2 inhibitors. (doi:10. References Arai  H.177) Balboa MA. Wagner  K.freeradbiomed. Karakurt F & Turhan NÖ 2011 Serum platelet-activating factor acetylhydrolase activity: relationship with metabolic snydrome in women with a history of gestational diabetes mellitus. (doi:10. Kawamura  T.0079233) De Luca D.12. Callaway LK & Dekker Nitert M 2014 Placental lipases in pregnancies complicated by gestational diabetes mellitus (GDM). Hayashi  K.1038/pr. McIntyre HD. Mattar R & Daher  S 2013 Cytokine levels in gestational diabetes mellitus: a systematic review of the literature. 2013.0b013e32832dd4c7) Gomes CP. and phase II trials on both compounds were stopped (Rosenson et  al. Puisieux A.

(doi:10. Tischfield JA & Kudo I 1998 The functions of five distinct mammalian phospholipase A2s in regulating arachidonicacid release and act in concert with cytosolic phospholipase. Journal of Biochemistry 150 233–255.1733) Lagos KG.272.107789) Kudo I & Murakami M 2002 Phospholipase A2 enzymes.2009.1074/ jbc.273. Giaid  A.0000000000000138) Rosenson  R. Rainey K. Korita D.1159/000293312) Pulkkinen  M. Sato  H & Yamamoto  K 2011b Secreted phospholipase A2 revisited.reproduction-online.1074/jbc. Davey Smith G.237.2003.009) Johansen B. Placenta 19 35–40. Kleimola V. Gumaa  K & Scioscia  M 2007 Preeclampsia. Vinturache A. Dabelea  D.07.org Phospholipase A2 in pregnancyR101 Moses  EK. Trends in Pharmacological Sciences 20 162–170. Rice  GE. Journal of Biological Chemistry 272 32315– 32320. Lindsay  RS.2006.32315) www. Prostaglandins & Other Lipid Mediators 60 119–125. Gynecologic and Obstetric Investigation 29 104–107.05. Miki Y. Brennecke  SP & Rice  GE 1998 Distribution of the phospholipase A2 receptor messenger RNA in human gestational tissues. Mosher A. Fraser  A. Kuwata H. Fraser  H.1007/s11745-008-3251-9) Lambeau G 1999 Receptors for a growing family of secreted phospholipases A2. Gynecologic and Obstetric Investigation 36 96–101. Fertility and Development 11 75–79. Taketomi Y. gestational diabetes and glycosuria in pregnancy with macrosomia and offspring body mass index. Pandit C.1126/ science. Hirabayashi T & Yamamoto K 2011a Recent progress in phospholipase A2 research: from cells to animals to humans.2000. Chaithra V. Arnold RD & Cummings BS 2014 Secretory phospholipase A2 enzymes as pharmacological targets for treatment of disease. Catalano  P. Shimoya K. Lajeunesse D.6.3. Nakatani Y. (doi:10. Murakami  M. Nakajima A. Mitsuishi  M. Lipids 44 9–16.23. Placenta 20 21–26. Leukotrienes and Essential Fatty Acids 70 87–100. Mounier  C & Franken  P 1996 The anticoagulant effect of the human secretory phospholipase A2 on blood plasma and on a cell-free system is due to a phospholipid-independent mechanism. Taketomi  Y. Pruzanski  W & Vadas  P 1991 Phospholipase A2–a mediator between proximal and distal effectors of inflammation. (doi:10. Journal of Biological Chemistry 271 30041–30051.0586) Lawlor  D. Tsimihodimos V. Berger  H & Walther  F 2008 Secretory phospholipase A2 in newborn infants with sepsis. (doi:10. Hattori K. (doi:10. Farrugia W.1067/mob.1998. (doi:10. Infection and Immunity 66 2791–2797. Winstead MV.272. insulin signalling and immunological dysfunction: a fetal. Ali  H. selective and non-selective non-steroidal anti-inflammatory drugs.2000. Placenta 22 64–69. Martel-Pelletier J. Murakami M & Kudo I 1998 Cytosolic phospholipase A2 is required for cytokine ninduced expression of type IIA secretory phospholipase A2 that mediates optimal cyclooxygenase-2-dependent delayed prostaglandin E2 generation in rat 3Y1 fibroblasts. Arai H & Inoue K 1997 Protection against oxidative stress-induced cell death by intracellular platelet-activating factor-acetylhydrolase II. Levinson H. during and after spontaneous-onset labour at term. Balboa M & Dennis E 2000 Expression of cytosolic and secreted forms of phospholipase A2 and cyclooxygenases in human placenta. (doi:10. Eskola J. fetal membranes. Azuma C. Marathe G. (doi:10. Annals of the Rheumatic Diseases 62 501–509. Prostaglandins & Other Lipid Mediators 68–69 3–58. Sattar N & Nelson SM 2010 Association of existing diabetes. Ishikawa  Y. Suehara N.16709) Lim  KH. Reproductive Sciences 2 921–929. Permezel  M.501) Masuda  S. Current Opinion in Endocrinology. Journal of Lipid Research 55 1847–1854.1053/plac.1042/BJ20041307) Matsuzawa A. de Beaufort  A.plefa. Itoh  H.1016/j.7211929) Reproduction (2016) 151 R91–R102 . Rakkestad K. Ness  A. (doi:10. International Journal of Nanomedicine 10 1985–1996. Riley B.1159/000292604) Qu  X & Lehrer  R 1998 Secretory phospholipase A2 is the principal bactericide for staphylococci and other gram-positive bacteria in human tears. Okumura  K. Seminars in Perinatology 39 20–26. Clinical Immunology 133 402–410. Gynecological Endocrinology 30 241–244. Journal of Biological Chemistry 273 1733–1740. labor and fetal outcome.issue-3) Munns MJ. (doi:10. Shimbara S. Kobayashi  F. (doi:10. Gazi IF. Diabetologia 53 89–97. (doi:10.1016/j.022) Rademacher  TW. Biochimica et Biophysica Acta 1761 1246–1259.2014. Denora  N & Rytting  E 2015 Oxcarbazepine-loaded polymeric nanoparticles: development and permeability studies across in vitro models of the blood–brain barrier and human placental trophoblast.1111/ejb.08. Science 256 1553–1555. American Journal of Obstetrics 183 1537–1543. Reproduction.0341) Murakami M. Kuwata H.47. Matsumoto  T. Goulder  M & Hislop  C 2011 Anti-inflammatory effects of varespladib methyl in diabetic patients with acute coronary syndrome. Katzman PJ 2015 Chronic inflammatory lesions of the placenta.271.1996. Simberg N & Thuren T 1990 Pancreatic and catalytic phospholipase A2 in relation to pregnancy. (doi:10.1598587) Leslie  C 1997 Properties and regulation of cytosolic phospholipase A2. (doi:10. (doi:10. Komiyama  K.011) Schrama  A. Prostaglandins. European Journal of Biochemistry 785 778–785.273. Wang  B & Wen  J 2014 Lipoprotein-associated phospholipase A2 and AGEs are associated with cardiovascular risk factors in women with history of gestational diabetes mellitus. Poorthuis  B.clim. (doi:10. Journal of Perinatology 28 291–296.001) Lappas  M. Kivikoski  A & Nevalainen T 1993 Group I and group II phospholipase A2 in serum during normal and pathological pregnancy.30041) Murakami M.62. (doi:10. Diabetes and Obesity 22 112–118. Lakshmikanth C. Medical Principles and Practice 22 (Supplement 1) 8–19. Raghupathy  R 2013 Cytokines as key players in the pathophysiology of preeclampsia.1074/jbc.jp. Biochemical Journal 387 27–38. Tselepis AD & Elisaf MS 2009 Alterations in the high density lipoprotein phenotype and HDL-associated enzymes in subjects with metabolic syndrome. Wood S & Slater DM 2014 Regulation of sPLA2-IID in human decidua: insights into the complexity of the prostaglandin pathway in labor.04.1016/j. lymphocytes are down-regulated in human miscarriage. Journal of Biological Chemistry 272 16709–16712.27. Sato H. (doi:10.1016/ S0165-6147(99)01300-0) Lappas  M & Rice  G 2004 Phospholipase A2 isozymes in pregnancy and parturition. (doi:10. (doi:10.1016/0002-9378(95)90033-0) Lopalco  A. Immunology Today 12 143–146.1074/ jbc. Aoki J. Ishii  T & Kudo I 2005 Expression of secretory phospholipase A(2) enzymes in lungs of humans with pneumonia and their potential prostaglandinsynthetic function in human lung-derived cells. Bennett  H. Jacob S & D’Souza C 2014 To hydrolyze or not to hydrolyze: the dilemma of platelet-activating factor acetylhydrolase. (doi:10. (doi:10.1136/ard.1159/000354200) Robichaud  P & Surette  ME 2015 Polyunsaturated fatty acidphospholipid remodeling and inflammation. Cardiovascular Drugs and Therapy 25 539–544. Sagawa  N. Journal of Biological Chemistry 273 14411– 14423.1097/ MED. Freed  KA.1007/ s10557-011-6344-2) Schaloske  RH & Dennis  EA 2006 The phospholipase A2 superfamily and its group numbering system. (doi:10.bbalip. (doi:10. Quach ND. Murakami  M.51. maternal or placental disorder? Journal of Reproductive Immunology 76 78–84. (doi:10. King RG & Rice GE 1999 Secretory type II PLA2 immunoreactivity and PLA2 enzymatic activity in human gestational tissues before. Mai  C. Murata Y & Tojo H 2000 Elevations of group II phospholipase A2 concentrations in serum and amniotic fluid in association with preterm labor.1053/plac.1038/sj.1007/s00125-009-1560-z) Lefebvre  D.14411) Murakami M. Koyama M.1016/j. American Journal of Obstetrics and Gynecology 172 998–1002. Kambe T. and chorionic cell lines. Nakatani Y & Kudo I 1996 Type II secretory phospholipase A2 associated with cell surfaces via C-terminal heparin-binding lysine residues augments stimulus-initiated delayed prostaglandin. Filippatos TD. Pulkkinen M. Ito S. Rizos C. Progress in Lipid Research 50 152–192. Tanada S & Mori T 1999 Activity of platelet-activating-factoracetylhydrolase and the nitric oxide metabolite level in the plasma of women who develop transient pregnancy hypertension during later pregnancy. Biochemical Pharmacology 90 338–348.1074/jbc. (doi:10.bcp. Reboul P & Pelletier J 2003 Therapeutic role of dual inhibitors of 5-LOX and COX. Georgiou  HM & Rice  GE 2001 Type II phospholipase A2 in preterm human gestational tissues. Nanno  H. Lariviere  R & Zingg  H 1992 Oxytocin gene expression in rat uterus. de Groot  CJ & Taylor  RN 1995 Plasma type II phospholipase A2 levels are elevated in severe pre-eclampsia. waist and fat mass in later childhood: findings from a prospective pregnancy cohort.

Zhou Y.2009. Tambaki AP. Lissauer  DM. Hefler  L. Maguire  CT. Lei Q.1016/j.0000169355.1097/01. Marta  DS. Cariolou MA. Serban  M. Bairaktari E. (doi:10. Journal of Pharmaceutical Sciences 100 3146–3159. (doi:10. Mello  APQ & Damasceno  NRT 2011 Antioxidant and inflammatory aspects of lipoprotein-associated phospholipase A2 (LpPLA2): a review. Stanescu  HC. Schimpf  B et  al.2013. Reardon  M.1038/ 374549a0) Tsimihodimos V. (doi:10. Wolfert  R. & Hauguel-de Mouzon S 2006 Activation of phospholipase A2 is associated with generation of placental lipid signals and fetal obesity.20395. (doi:10. Radaelli T.1093/molehr/ gah103) Song  H. Geis  R. 2011 Risk HLA-DQA1 and PLA2R1 alleles in idiopathic membranous nephropathy. Journal of Lipid Research 50 3–21.1021/mp2000742) van der Helm  H. Stoian  I. Schatten  C. Aljuffali I. Arcos-Burgos  M.15. Vickers  KC. Zeisler  H. Molecular Human Reproduction 10 799–805. Dietsch  G. Heart and Vessels 30 1–7. Holvoet P & Morrisett JD 2009 Relationship of lipoprotein-associated phospholipase A2 and oxidized low density lipoprotein in carotid atherosclerosis. Lin X.org . Van Tomme SR. Bockenhauer  D. Karabina S-AP.issue-4) Silva  IT. Kume  K. Plant  S. Mock JN.55) Yasuda  K & Okumura  T 2001 Platelet-activating factor acetylhydrolase isoforms I and II in human uterus. mol.1186/ 1476-511X-10-170) Slater DM.005) Varastehpour A. Nagase  T & Nakatani  N 1997 Role of cytosolic phospholipase A2 in allergic response and parturition. Goudevenos JA. (doi:10. Miltiadous G. Chapman MJ.2002. (doi:10.1056/ NEJMoa1009742) Tamblyn  JA. Minium J. Husslein  P & Kainz  C 2001 Synovial phospholipase A 2 serum levels in pregnancy and preeclampsia. Neys  F & van den Bosch  H 1996 Regulation of the expression of group IIA and group V secretory phospholipases A 2 in rat mesangial cells. Eberhardt  C. Journal of Biochemistry 106 38–42.2007.275. Zhou Y. Journal of Biological Chemistry 275 10876–10886.002) Tellis  CC & Tselepis  AD 2009 The role of lipoprotein-associated phospholipase A2 in atherosclerosis may depend on its lipoprotein carrier in plasma.22530) Received 3 November 2015 First decision 5 January 2016 Revised manuscript received 11 February 2016 Accepted 22 February 2016 www. Nuijen B.07.1016/j. Catalano P. Stefanski  E.reproduction-online. Pruzanski  W.1111/jcmm. Acta Obstetricia et Gynecologica Scandinavica 80 27–29. Kottgen  A. Schilling  J. (doi:10. Nature 390 618–622. Molecular Pharmaceutics. Journal of Lipid Research 50 1735–1743.1016/j.6.1002/jps. Biochimica et Biophysica Acta 1761 1373–1382. Biochimica et Biophysica Acta 1791 327–338. Herrera E.003) Yu J.1. 2002 Altered distribution of platelet-activating factoracetylhydrolase activity between LDL and HDL as a function of the severity of hypercholesterolemia.2006. Powell  R. Zechner  R. Current Opinion in Lipidology 16 341–344. Beijnen JH & Storm  G 2011 Liposomal drug formulations in the treatment of rheumatoid arthritis. Tanaseanu  C. Lv L & Chen L 2014 Lipoproteinassociated phospholipase A2 is associated with postpartum hypertension in women with history of preeclampsia. Cohen  Y & Shoseyov  D 2006 Control of phospholipase A2 activities for the treatment of inflammatory conditions. Metselaar JM. Journal of Huazhong University of Science and Technology 33 725–729. Wilder  C. Reproduction (2016) 151 R91–R102 Uozumi  N. (doi:10. Goudevenos JA.015) Tempfer  C.1080/791201829) Thomas  G. Lipids in Health and Disease 10 170.R102 C Besenboeck and others Seilhamer  JJ. Bennett PR & Thornton S 2004 Labour is associated with increased expression of type-IIA secretory phospholipase A2 but not type-IV cytosolic phospholipase A2 in human myometrium. Janssen  M. (doi:10. Paria  BC. Massachusetts Medical Society 364 616–626. Biochimica et Biophysica Acta 1484 215–224. Placenta 34 846–855. Cox  P & Kilby  MD 2013 The immunological basis of villitis of unknown etiology – review. Comparisons with pregnant uterus and myoma. Gui J. Astle S. (doi:10. Journal of Cellular and Molecular Medicine 6 643–647. Kosaka  T. Li A. Matsumoto  H & Swift  LL 2002 Cytosolic phospholipase A 2 α deficiency is crucial for “on-time” embryo implantation that directs subsequent development. New England Journal of Medicine. Burns  AR. Zimmermann  R & Lass  A 2009 Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. Biology of Reproduction 64 339–344. Niu J. 1995 Anti-inflammatory properties of a plateletactivating factor acetylhydrolase.08.1677/ ERC-07-0253) Webb  N 2005 Secretory phospholipase A2 enzymes in atherogenesis. Vidulescu  C.bbalip. Wen J. (doi:10. Ortega H. Nature 374 549–553.10876) Tjoelker  LW. (doi:10.bbalip.placenta.1016/ j.07. Bertrand  F & Saunier  B 2000 The differential regulation of group IIA and group V low molecular weight phospholipases A2 in cultured rat astrocytes. Cummings BS & Arnold RD 2011 Secretory phospholipase A(2) responsive liposomes. Dragomirescu  L et  al.tem. Kienesberger  PC. Lim  H. Journal of Clinical Endocrinology & Metabolism 91 248–255.1038/37622) van den Hoven JM. Zhu G. Duan D. Tselepis AD et al.02. American Chemical Society 8 1002–1015. Stafforini  DM. Journal of Lipid Research 43 256–263. (doi:10.339) Yedgar  S.1074/jbc. Medlar  A. Tanaseanu S & Moldoveanu E 2002 Significance of platelet-activating factor acetylhydrolase in patients with non-insulin-dependent (type 2) diabetes mellitus. (doi:10. (doi:10. Vadas  P & Johnson LK 1989 Multiple forms of phospholipase A2 in arthritic synovial fluid. Development 129 2879–2889. Haemmerle  G. (doi:10. (doi:10. Aarsman  A. Su X & Feng L 2013 Assessment of the number and function of macrophages in the placenta of gestational diabetes mellitus patients.1095/ biolreprod64.