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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 1 433-439
Copyright © 2003 by The Endocrine Society

Original Article

Expression and Localization of Prostaglandin E Synthase Isoforms in Human Fetal Membranes in Term and Preterm Labor

Juliana W. Meadows, Annie L. W. Eis, Diane E. Brockman and Leslie Myatt

Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, Ohio 45267-0528

Address all correspondence and requests for reprints to: Leslie Myatt, Ph.D., University of Cincinnati, College of Medicine, Department of Obstetrics and Gynecology, 231 Albert Sabin Way, Cincinnati, Ohio 45267-0526. E-mail: leslie.myatt{at}uc.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Increased prostaglandin (PG) synthesis by fetal membranes occurs at parturition. PGE2 synthesis from arachidonic acid involves multiple enzymes and two isoforms of the terminal enzyme of this biosynthetic pathway, PGE synthase (PGES), were recently identified. Cytosolic PGES (cPGES) is identical to the heat shock protein 90 chaperone, p23, and is reportedly functionally coupled to constitutive PG endoperoxide H synthase-1. Microsomal PGES (mPGES) is inducible by proinflammatory cytokines such as IL-1ß. We have studied expression and localization of both enzyme isoforms in human fetal membranes either at term or preterm, with or without labor. The cPGES was immunolocalized in the amnion epithelium, and associated with fibroblasts and macrophages in the choriodecidual layer, whereas mPGES was localized in the amnion epithelium as well as the chorion trophoblast. Both enzymes were found to be associated with lipid particles present in the amnion epithelium, which are more prevalent in term tissues. Western blot analysis of the amnion and choriodecidua showed no differences in amounts of either cPGES or mPGES at term or preterm, with or without labor, in either tissue with advancing gestation. It does not appear that expression of PGES is the rate-limiting step in PGE2 synthesis in fetal membranes at labor.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PROSTAGLANDIN (PG) PRODUCTION from arachidonic acid by intrauterine tissues at parturition plays a role in the initiation and maintenance of labor. The conversion of arachidonic acid to PGH2 is catalyzed by one of the two isoforms of the prostaglandin H synthase enzyme, PGHS. PGHS-1 is constitutively expressed in many tissues and cells, whereas PGHS-2 can be induced by proinflammatory cytokines such as IL-1ß at sites of inflammation. The increase in PG synthesis at parturition is associated with increased expression of the enzyme PGHS-2 (1, 2, 3, 4, 5, 6). Downstream of the PGHS enzyme isoforms, the PGH2 product can be further metabolized into various physiologically important eicosanoids such as PGE2, PGF2{alpha}, PGD2, prostacyclin (PGI2) and thromboxane A2 (TXA2) by various specific synthases (7).

Recently, PGE synthase (PGES), the enzyme responsible for the conversion of PGH2 to PGE2, was isolated and two isoforms identified: cytosolic (cPGES) and microsomal (mPGES). Cytosolic PGES is identical to p23, a putative 23-kDa chaperone molecule that binds to heat shock protein (hsp90) (8) and is constitutively expressed, with expression not being affected by proinflammatory stimuli in various human and animal tissues and cell lines (9). However, in rat brain, cPGES mRNA level increased after treatment with lipopolysaccharide (LPS), consistent with elevated PGES activity detected in the brain cytosol (9). This enzyme isoform was reported to be preferentially associated with PGHS-1 (10), suggesting functional coupling. Jakobsson et al. (11) identified and characterized the human mPGES, a 16-kDa protein that is most closely related to the microsomal glutathione transferase-1, an inducible member of the membrane-associated proteins involved in eicosanoid and gluthathione metabolism superfamily (12, 13, 14). In human alveolar A549 cells, mPGES activity and protein levels were dramatically increased in the presence of IL-1ß (8), and this increase was prevented with the addition of phenobarbital (13). Rat mPGES, which has 80% identity to the human enzyme at the amino acid level, showed a similar pattern of induction following LPS treatment. Rat mPGES mRNA was up-regulated in the lung, colon, brain, heart, testis, spleen, and seminal vesicles (15). Microsomal PGES has been shown to be functionally linked to PGHS-2 in LPS- and IL-1ß-induced PGE2 production in various rat tissues (16, 17, 18, 19, 20).

PGs are not stored but are synthesized and released. Marked increases in PG concentration in the amniotic fluid and serum have been reported with advancing gestation and labor, suggesting the important role of PGs in initiation of labor (21). This increase in PGHS activity was due to an increase in PGHS-2 expression, which occurs primarily in fetal tissues (1, 18). PGE2 synthesis by intrauterine tissues increases at term with labor, and the amnion is recognized to be a major site of PGE2 production (22). However, there is no information pertaining to the expression and activity of PGES in relation to PGE2 production in humans during labor. This study was designed to examine the localization and expression of PGES isoforms in human fetal membranes. We hypothesized that both PGES enzyme isoforms are found in the human fetal membranes and expression of the enzymes in the amnion and chorion is increased with advancing gestation and labor.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials

Rabbit antihuman PGES polyclonal antibody was purchased from Cayman Chemical (Ann Arbor, MI), and mouse monoclonal anti-p23 from Affinity BioReagents, Inc. (Golden, CO). Protease inhibitors including pepstatin, leupeptin, 4-(2-aminoethyl) benzenesulfonyl fluoride, N{alpha}-p-tosyl-L-lysine-chloromethyl ketone, and sodium orthovanadate were purchased from Calbiochem (San Diego, CA). Recombinant IL-1ß was purchased from Biosource Technologies, Inc. International (Camarillo, CA). Prestained low-molecular-weight marker and Tris-glycine gels were obtained from Bio-Rad Laboratories, Inc. (Hercules, CA) and Invitrogen (Carlsbad, CA), respectively. Vectastain Elite ABC and aminoethyl carbazole (AEC) were purchased from Vector Laboratories, Inc. (Burlingame, CA), and hematoxylin was obtained from Biomeda Corp. (Foster City, CA).

Tissue collection and preparation

Tissues were collected according to the guidelines set forth in the protocol that is in compliance with the Institution Review Board of University of Cincinnati (Cincinnati, OH). Human fetal membranes (n = 5 patients per group) were collected immediately after delivery at term following labor (39 ± 1.7 wk), term with no labor (38.2 ± 0.9 wk), preterm following labor (29.3 ± 4.2 wk), and preterm no labor (30.8 ± 3.3 wk). For immunohistochemistry, a 3- to 6-cm strip of reflected membranes was cut, rolled, flash frozen in liquid nitrogen, and stored at -80 C. Cryosections (7 µm) of membrane rolls were cut just before immunostaining.

For SDS-PAGE analysis, separated amnion, and choriodecidua were flash frozen in liquid nitrogen and stored at -80 C. The amnion and choriodecidua samples (n = 4 patients per group) were homogenized at 4 C in homogenizing buffer [250 mM sucrose and 50 mM HEPES (pH 7.4)] with a hand-held Tissue Tearor (speed 18) in the presence of protease inhibitors (0.7 µg/ml pepstatin, 10 µg/ml leupeptin, 200 µM leupeptin, 4-(2-aminoethyl) benzenesulfonyl fluoride, 100 µM N{alpha}-p-tosyl-L-lysine-chloromethyl ketone, and 200 µM sodium orthovanadate) and centrifuged at 1000 x g for 15 min at 4 C. The supernatant was ultracentrifuged at 100,000 x g for 1 h at 4 C to obtain the cytosolic and microsomal fractions for SDS-PAGE.

Immunohistochemistry

Cryosections of membrane rolls were immunostained as described previously (23). Briefly, serial frozen sections were allowed to air dry, hydrated, and immunostained using the Vectastain Elite ABC method with the mouse kit for the monoclonal antibody against cPGES (p23) and the rabbit antibody kit for polyclonal anti-PGES. For all immunostaining, 0.1% of saponin was included in all solutions until the application of ABC complex. An irrelevant mouse IgG raised against Aspergillus niger glucose oxidase and purified preimmune rabbit IgG were used as negative immunological control for cPGES and mPGES, respectively, on serial sections.

After air drying, all slides were blocked using the respective animal serum corresponding to the secondary antibody for 30 min at room temperature. Excess blocking solution was removed and respective primary antibody was added with incubation overnight at 4 C. The slide was rinsed for three 5-min cycles in PBS. Incubation with secondary antibody was at 37 C for 60 min. All slides were then rinsed for 5 min three times in PBS. The ABC complex was incubated with all slides for 30 min at room temperature, followed by three 5-min rinse cycles in PBS. AEC was used as peroxidase substrate and allowed to develop for 5–10 min. The slides were then rinsed with filtered water (Millipore Corp., Bedford, MA) and counterstained with hematoxylin for 3 min and then mounted in 1:9 PBS/glycerol.

Tissue sections were also stained for the presence of lipid droplets using the Sudan Black B method (24). Briefly, cryosections were air dried and hydrated in PBS for 5 min. The sections were incubated in Sudan Black B for 10 min, followed by a quick rinse in 70% ethanol and water. The sections were counterstained with Mayer’s Carmalum for 30 min, rinsed, and mounted in 1:9 PBS/glycerol.

SDS-PAGE and Western blotting

Cytosolic and microsomal samples of the amnion and choriodecidua were diluted in 2x sample buffer, containing 0.25 M Tris (pH 6.8), 20% glycerol, 2% SDS, 5% ß-mercaptoethanol, and 0.02% bromophenol blue and heated at 100 C for 5 min. Protein samples were loaded (10 µg per lane); separated using 18% Tris/glycine gels (Invitrogen), and run at 40 mA/gel. Prestained low-molecular-weight markers (Bio-Rad Laboratories, Inc.) were loaded as standards. The gels were then electroblotted onto nitrocellulose membranes (Osmonics, Inc.). The blots were blocked for 1 h in Tris-buffered saline (TBS) consisting of 100 mM TrisHCl, pH 7.5, 150 mM NaCl containing 0.1% (vol/vol) Tween 20, and 5% (wt/vol) nonfat dried milk at room temperature with agitation. The blots were then incubated with 1:1000 dilution of anti-PGES (0.5 µg/ml, Cayman Chemical) or anti-cPGES (1:1000 dilution) for 1 h and overnight at 4 C, respectively. The blots were washed three times in TBS containing 0.1% (vol/vol) Tween 20 and incubated for 1 h at reverse transcription with horseradish peroxidase-conjugated donkey antirabbit (1:1000) and donkey antimouse (1:1000) for mPGES and cPGES, respectively, in TBS with 5% nonfat dry milk. The washing steps were repeated, and the enhanced chemiluminescence (ECL) detection system (Amersham, Piscataway, NJ) was used to identify the presence of bands. The resulting band intensities were quantitated using an {alpha} imager 5.0 scanning densitometer (Alpha Innotech Corp., San Leandro, CA). A549 cell lysates were used as positive control for mPGES expression. Statistical differences between groups were analyzed using Kruskal-Wallis ranked ANOVA as a nonparametric method.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The microsomal PGES isoform was immunolocalized to the amnion epithelium and chorion trophoblast of the fetal membranes, both at term and preterm, either with or without labor (Fig. 1Go, data not shown for without labor). In tissues obtained from the preterm labor group, mPGES was localized in the amnion epithelium and chorion trophoblast (Fig. 1AGo). At higher magnification, the cytoplasm of the amnion epithelial cells (Fig. 1BGo) and the chorion trophoblast cells (Fig. 1CGo) appear to be uniformly stained for mPGES. In the term labor group, distinct staining of mPGES was observed in the amnion epithelium (Fig. 1Go, E–F) as well as in the chorion trophoblast (Fig. 1Go, E and G). However, we also observed punctate staining of mPGES in term labor tissues, compared with preterm tissues. These punctate staining patterns seem to coincide with lipid droplets in the amnion epithelium and chorion trophoblast. A specific method for staining lipid was performed to verify the presence and location of lipid particles in fetal membranes obtained from patients at term. Lipid droplets in term labor tissues stained with Sudan Black B appeared blue, and nuclei counterstained with Mayer’s Carmalum appeared pink. The amnion epithelium and chorion trophoblast was heavily populated with these lipid droplets as seen in Fig. 2Go, A and B, respectively, and they seem to coincide with the location of both enzyme isoforms in term tissues, either with or without labor. Staining of mPGES seemed to localize primarily in the amnion epithelium and chorion trophoblast in term and preterm tissues, with or without labor. However, a noted difference between term and preterm labor tissues was the apparent association of the mPGES enzyme isoform with lipid droplets in the amnion epithelium and chorion trophoblast, which was not seen in the preterm tissues, either with or without labor (Fig. 1Go, B and C, E and F). Corresponding negative controls with purified preimmune rabbit IgG (Fig. 1Go, D and H) showed no staining in the amnion epithelial or chorion trophoblast, except for faint staining in the subepithelial amnion fibroblast.



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  		Figure 1. Immunolocalization of mPGES in fetal membranes. Microsomal PGES was found extensively in the amnion epithelium and chorion trophoblast of the fetal membranes. Intense staining was observed in all tissue samples, with no significant differences observed between samples, preterm labor (A–C) and term labor (E–G). All tissue sections were counterstained with hematoxylin. Negative immunological controls (D and H) show little or no staining in fetal membranes.

 


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  		Figure 2. Sudan Black B staining of lipid particles in term labor fetal membranes. Lipid droplets were stained dark blue with Sudan Black B in the amnion epithelium (A) and chorion trophoblast (B) of all five tissue groups. The nuclei were counterstained with Mayer’s Carmalum (pink).

 
Cytosolic PGES immunostaining was found in the amnion epithelium in both preterm labor and term labor tissues (Fig. 3Go, nonlabor data not shown). In addition, immunostaining of the fibroblasts and macrophages within the chorion trophoblast layer was also seen. Intense staining of cPGES was also observed in a fibrin clot (Fig. 1CGo). With term labor tissues (Fig. 3Go, E–G), punctate staining was again observed in the amnion epithelium, possibly showing association of cPGES with lipid particles present in the fetal membranes. Negative immunological controls using an irrelevant mouse IgG (Fig. 3Go, D and H) showed no staining in the fetal membranes demonstrating specificity of cPGES localization.



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  		Figure 3. Immunolocalization of cPGES in the amnion epithelium, fibroblasts, and activated macrophages within the chorion trophoblast of fetal membranes. A–C, preterm labor; E–G, term labor. No visible staining was observed in the negative controls (D and H).

 
Microsomal and cytosolic protein fractions of amnion and choriodecidual samples from both term and preterm, with and without labor patient groups, were separated on 18% Tris/glycine gel and immunoblotted with anti-PGES and anti-cPGES antibodies. Immunoreactive bands of the expected sizes of 16 kDa (mPGES) (Fig. 4Go, A and B), which corresponded to the standard protein from A549 cells, and 23 kDa (cPGES) (Fig. 4Go, C and D) were seen on the gels. Both the microsomal and cytosolic fractions from each tissue showed expression of both mPGES (Fig. 4Go, A and B) and cPGES (Fig. 4Go, C and D). Scanning densitometry revealed no apparent differences in band intensities between the groups of tissues as confirmed by Kruskal-Wallis ranked ANOVA (P > 0.05; data not shown).



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  		Figure 4. Western blot analysis of mPGES (A and B) and cPGES (C and D) expression in amnion and choriodecidua of preterm and term, labored and nonlabored tissues. Microsomal (A and C) and cytosolic (B and D) fractions of the amnion and choriodecidua were analyzed by SDS-PAGE and Western blotting (10 µg protein per lane). Both fractions of the amnion and choriodecidua sample expresess mPGES and cPGES enzyme isoforms. No significant differences in enzyme expression were observed between tissue samples. PTL, Preterm labor; PTNL, preterm no labor; TL, term labor; TNL, term no labor.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The control of the timing of labor is complex and involves interaction of the mother, fetus, placenta, and membranes. It is known that PGs are involved in the final common pathway of uterine contractility and parturition (25). An increase in PG synthesis by the fetal membranes and placenta at term, which occurs before and during labor, is also well documented (26). This increase is attributed to up-regulation of PGHS-2 levels and activity in the fetal membranes. PGHS-2 is responsible for the conversion of arachidonic acid, released by the action of cytosolic phospholipase A2, to PGH2. The subsequent enzyme step would involve either cytosolic or microsomal PGES in the conversion of PGH2 to PGE2.

Expression of both PGES enzyme isoforms was observed in human fetal membranes throughout gestation suggesting that increased PGE2 production during labor could be attributed to the activity of either or both of these enzyme isoforms. We localized both PGES enzyme isoforms in the amnion epithelium of the fetal membranes, a site rich in the arachidonic acid precursor for PGE2 production. In addition, we also localized mPGES to the chorion trophoblast of the fetal membranes, but cPGES was found to be associated with fibroblasts and macrophages within the choriodecidual layer. Immunostaining for both mPGES and cPGES was found in tissues from all four experimental groups, term and preterm, with or without labor, with no apparent difference in tissue localization with advancing gestation or labor. However, we did notice a shift in the intracellular localization of enzymes from preterm labor to term labor tissues. Localization of both enzyme isoforms seemed to change from a uniform distribution of staining in the cell cytoplasm of preterm tissues to a punctate staining pattern in the term labor tissues. The punctate pattern of staining was more pronounced for mPGES, compared with cPGES. This shift in staining pattern seems to coincide with the increased presence of lipid particles within the fetal tissues. Both enzyme isoforms appeared to be associated with these lipid droplets at term with labor, suggesting that the droplets could serve as a source of arachidonic acid for PGE2 production (27). Sonek et al. (28) had previously shown that lipid particles were increased in amnion epithelial of patients in labor but had not distinguished the difference between preterm and term labor. These lipid droplets may be indicative of apoptosing or growth-arrested cells (29, 30, 31). It is also possible that these lipid droplets could be involved in signal transduction and metabolism (32, 33, 34).

Western blot analysis of the amnion and choriodecidua samples from all four tissue groups confirmed the presence of both PGES enzyme isoforms in the fetal membranes as shown by immunohistochemistry. Both PGES isoforms were found to be expressed in the cytosolic and microsomal fractions of the amnion and choriodecidua of the fetal tissues. However, no significant difference was found in the level of expression for either enzyme isoform, either at term or preterm, with or without labor. Previous studies on either cytosolic or microsomal PGES were performed using only one of the isoforms to investigate the function and characterization of the enzyme; here we report that both enzyme isoforms were simultaneously detected in both cytosolic and microsomal fractions of the fetal membrane samples. The enzyme isoforms were present in similar amounts in both cytosolic and microsomal fractions, with no change in expression level at different gestation periods, with or without labor. Although concentrations of enzyme protein were unaltered during labor, a time when PGE2 production is increased, we cannot measure the enzyme activities of each PGES isoform separately during this time period. The presence of both PGES enzyme isoforms in the amnion epithelial of fetal membranes reinforces the concept that a primary site for PG synthesis at term and during labor in human is the fetal membranes. Although no significant changes in protein expression were observed in both cytosolic and microsomal fractions of amnion and chorion at term or preterm, the catalytic activity of the two enzyme isoforms at this stage is unknown. The fact that we see no difference in PGES at the protein level suggest that the rate-limiting step of PGE2 synthesis at labor lies with the cytosolic phospholipase A2 and PGHS-2 enzymes, not with PGES.


   Acknowledgments
 


   Footnotes
 
This work was supported by NIH RO1 Grant HD31514.

Abbreviations: cPGES, Cytosolic PGES; mPGES, microsomal PGES; PG, prostaglandin; PGES, PGE synthase; PGIA2, prostacyclin; TXA2, thromboxane A2.

Received July 8, 2002.

Accepted September 27, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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