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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 7 2289-2293
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

Transcriptional Regulation of Prostaglandin-H Synthase-2 Gene in Human Trophoblasts1

Eyal Y. Anteby, Roger D. Johnson, Xiahoua Huang, D. Michael Nelson and Yoel Sadovsky

From the Department of Obstetrics and Gynecology, Washington University School of Medicine,St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Yoel Sadovsky, M.D., Department of Obstetrics and Gynecology, Washington University School of Medicine, Box 8064, 4911 Barnes Hospital Plaza, St. Louis, Missouri 63110. E-mail: sadovsky-y{at}kids.wustl.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Abnormal PG production by placental PG-H synthase (PGHS) is associated with preeclampsia. There are two PGHS isozymes, and their regulation in trophoblasts is presently unknown. We hypothesized that the PGHS isozymes are differentially regulated in human trophoblasts. To test this hypothesis, we transfected primary trophoblasts and JEG3 cells with promoter constructs of either PGHS-1 or PGHS-2 genes. We found that in both cell systems, the basal activity of PGHS-2 promoter was 10- to 30-fold higher than the activity of PGHS-1 promoter. In response to either 12–0-tetradecanoylphorbol-13-acetate (TPA) or 8-bromo-cAMP, we observed an increase in PGHS-2 promoter activity but no change in activity of PGHS-1 promoter. Similarly, both agents enhanced PGHS-2 expression, as well as prostaglandin E2 production. The activity of PGHS-2 promoter was potentiated by coexpression of protein kinase A and inhibited by coexpression of kinase A inhibitor. Aspirin attenuated the stimulatory effect of TPA on PGHS-2 promoter. We conclude that both PGHS-1 and PGHS-2 promoters are active in trophoblasts. The activity of PGHS-2 promoter is stimulated by either TPA or cAMP, and the stimulatory effect of TPA is attenuated by aspirin. These pathways may play a role in modulation of prostanoid synthesis by trophoblasts.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PREECLAMPSIA complicates 7–10% of pregnancies and is a major cause of maternal complications, fetal growth restriction, and indicated premature delivery (1). Preeclampsia is associated with vasoconstriction, which is partly attributed to an altered ratio of thromboxane to prostacyclin (2). Aspirin, used for the prevention of preeclampsia, inhibits the activity of PG-H synthase (PGHS) and decreases PG and thromboxane synthesis (3, 4). An increase in thromboxane synthesis has been demonstrated in trophoblasts from preeclamptic patients and may contribute to the prostanoid imbalance observed in this disease (2, 5, 6). We recently identified an increase in PGHS-2 expression by trophoblasts from patients with preeclampsia (Johnson et al., submitted).

PGHS is a rate-limiting enzyme in the biosynthesis of PGs and thromboxane from arachidonic acid (7). There are two PGHS isozymes, which are encoded by two differentially regulated genes. PGHS-1 is generally constitutively expressed, whereas PGHS-2 expression is rapidly induced by inflammatory mediators, growth factors, mitogens, and hormones (7). Though clearly relevant to placental prostanoid production, the regulation of PGHS-1 and PGHS-2 genes in trophoblasts has not been previously investigated. We used a transient transfection system to study the transcriptional regulation of PGHS-1 and PGHS-2 genes in primary human trophoblasts and JEG3 placental line. We then correlated the promoter activity with enzyme expression and prostaglandin E2 estradiol (PGE2) production.


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

The study was approved by the Human Studies Committee at Washington University. Cytotrophoblasts were isolated from placentas of term, singleton deliveries by the trypsin-deoxyribonuclease, percoll-gradient centrifugation method of Kliman et al (8) and plated in Ham’s-Waymouth media, supplemented with L-glutamine and antibiotics in a 5% CO2 incubator. The results were reproduced using media-199 in the presence or absence of 10% FBS. The results also were confirmed using trophoblasts that were purified using the technique described by Douglas and King (9), designed to eliminate the small population of nontrophoblastic cells. JEG3 cells were cultured in a modified Eagle’s medium with 10% FBS and antibiotics. Cells were treated with 12–0-tetradecanoylphorbol-13-acetate (TPA), 8-bromo-cAMP, aspirin (all from Sigma, St. Louis, MO), or interleukin-1 ß (IL-1ß, Genzyme, Cambridge MA).

Plasmids and transfections

The PGHS-1 promoter (-789/9 fragment) and the PGHS-2 promoter (-891/9 fragment), cloned upstream of the firefly luciferase gene in a pXP1 vector, were kindly provided by L. H. Wang (10, 11). Expression vectors for the catalytic subunit of a cAMP-dependent protein kinase A (PKA) and its specific inhibitory peptide (12), protein kinase inhibitor (PKI), were kindly provided by R. Maurer (13). In preliminary studies, we established that, for efficient transfection of trophoblasts, the calcium phosphate coprecipitation method (14) was superior to either electroporation (15), lipofection (Invitrogen, San Diego, CA), or direct gene transfer using a particle bombardment device (16) (data not shown). For transfection, primary trophoblasts (1.3 x 106 cells/cm2) or JEG3 cells (7 x 104 cells/cm2) were seeded in duplicate on 12-well polystyrene plates for 24 h. A total of 0.6 µg of plasmid DNA per well was transfected. The medium was replaced after 16 h, and ligands were added. After an additional 24 h, the cells were lysed and assayed for luciferase activity using a luminometer (Monolight 2010, Analytical Luminescence Laboratory, San Diego, CA). To normalize for cell number and transfection efficiency, the cells were cotransfected with an RSV ß-galactosidase (ß-gal) reporter vector. ß-gal activity was determined using a plate reader (anthos htIII, Salzburg, Austria). Each experiment was performed in duplicate and repeated at least three times using different placentas.

Northern blot analysis

PGHS-2 complementary DNA (cDNA) was kindly provided by M. J. Holtzman, and a SalI 1.8-kb fragment was used as a probe. PGHS-2 and cyclophilin (17) cDNA probes were labeled with 32P (1 x 106 cpm/mL) using an oligolabeling kit (Pharmacia, Piscataway, NJ). Primary trophoblasts (2 x 106 cells/cm2) or JEG3 cells (1 x 106 cells/cm2) were plated in duplicates on 10-mL plates. Ligands were added 24 h after seeding, and cells were harvested 24 h later. Poly-A messenger RNA (mRNA) was isolated by the guanidine isothiocyanate/oligo (deoxythymidine)-cellulose chromatography in a spun column format (Pharmacia). The isolated RNA (3 µg) was separated in a 1% denaturing agarose gel, which contained 1.5% formaldehyde, and transferred onto a nylon membrane (Duralon-UV, Stratagene, La Jolla, CA). Blots were hybridized in 50% formamide at 42 C overnight, then extensively washed, and exposed to Kodak XAR film (Kodak, Rochester, NY) for 24–96 h at -80 C. PGHS-2 and cyclophilin bands, detected on the same blot, were quantified using a densitometer.

RIA

PGE2 concentration in the medium was determined using RIA (PerSeptive Diagnostics, Cambridge, MA), following the manufacturer’s instructions. PGE2 levels were normalized to cellular protein and measured using the Bio-Rad protein assay (Bio-Rad, Hercules, CA). The inter- and intraassay variations were 7.2% and 12.4%, respectively.

Statistics

Data are presented as mean \ SD, and results were analyzed using the Student’s t test, with P < 0.05 determined significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We used the calcium phosphate coprecipitation method to transiently transfect either PGHS-1 (-789/9) or PGHS-2 (-891/9) promoters, cloned upstream of the firefly luciferase reporter plasmid, into primary trophoblasts obtained from term, healthy, singleton deliveries. The PGHS-1 and PGHS-2 promoter fragments previously were shown to be highly active in human endothelial cells or monocytes (11, 12, 18, 19). Though both promoters were active in primary trophoblasts, the activity of PGHS-1 promoter was relatively low (2-fold over the activity of the promoterless pXP1 vector). In contrast, the activity of PGHS-2 promoter was 10–30 times higher than the activity of PGHS-1 promoter (Fig. 1Go). We also screened JAr, BeWo, and JEG3 placental cell lines for constitutive activity of PGHS-1 and PGHS-2 promoters. We found the highest activity of both promoters in JEG3 cells. Again, the promoter activity of PGHS-2 was 10 times higher, compared with the activity of PGHS-1 (Fig. 1Go).



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  		Figure 1. The basal activity of the promoters for PGHS-1 and PGHS-2 genes in primary human trophoblasts and JEG3 cells. The promoters of either PGHS-1 (-789/+9 bp) or PGHS-2 (-891/+9 bp), cloned up-stream of luciferase in pXP1, were transfected into placental cells. Promoter activity was determined 48 h after transfection. Values were normalized to ß-gal activity from a cotransfected RSV ß-gal vector. The activity of PGHS-1 promoter was 2-fold above the activity of a promoterless pXP1 luciferase vector. Results (mean ± SD) are expressed as relative luciferase units (RLU) and represent three independent experiments, each performed in duplicate. The differences between PGHS-1 and PGHS-2 were significant at P < 0.0001.

 
Next, we tested for the transcriptional regulation of placental PGHS genes by either TPA (25 ng/mL) or 8-bromo-cAMP (1 mmol/L), both known to stimulate PGHS-2 expression in nonplacental tissues (7, 19, 20, 21, 22). We also tested for the effect of IL-1ß (10 ng/mL), which enhances PG production in trophoblast (23). As shown in Fig. 2AGo, either TPA or 8-bromo-cAMP stimulated PGHS-2 promoter activity by 4–5 fold. This stimulation was observed over 2–48 h (data not shown). In contrast, IL-1ß had no effect on the activity of PGHS-2 promoter. Similarly, as shown in Fig. 2BGo, the activity of the PGHS-2 promoter in JEG3 cells was induced by TPA (2-fold) or by cAMP (7-fold). The constitutive activity of PGHS-1 promoter in either cells was not influenced by any of the three ligands. We conclude that, in human trophoblasts, the activity of PGHS-2, but not PGHS-1, promoter is stimulated by TPA and cAMP.



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  		Figure 2. The effect of TPA, cAMP, or IL-1ß on the activity of PGHS-1 and PGHS-2 promoters in either primary human trophoblasts (A) or JEG3 cells (B). The promoter for PGHS-1 (-789/+9 bp) or PGHS-2 (-891/+9 bp), cloned up-stream of luciferase in pXP1, were transfected into trophoblasts. After transfection, the cells were incubated for 24 h with either 25 ng/mL TPA, 1 mmol/L 8-bromo cAMP, 10 ng/mL IL-1ß, or vehicle control. Values were normalized to ß-gal activity from a cotransfected RSV ß-gal vector. Results (mean ± SD) are expressed as relative luciferase units (RLU) and represent three independent experiments, each performed in duplicate. The differences between cAMP or TPA and control were significant at P < 0.05.

 
To determine whether the enhancement of PGHS-2 promoter activity by either TPA or cAMP led to increased expression of PGHS-2 gene, we measured PGHS-2 mRNA in trophoblast. As shown in Fig. 3Go, PGHS-2 was not expressed in COS7 cells (negative control) and highly expressed in human tracheal epithelial cells (positive control). Exposure to either TPA or 8-bromo cAMP caused an increase in PGHS-2 mRNA levels by five-fold or two-fold, respectively, over control. Correspondingly, we observed a 1.6-fold increase in PGE2 production by trophoblasts in response to TPA, and a 2.3-fold increase in response to cAMP (Fig. 4Go). Taken together, these findings indicate that the enhanced transcription of PGHS-2 promoter by TPA and cAMP increased the expression of a functional PGHS-2 protein.



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  		Figure 3. Induction of PGHS-2 mRNA in primary human trophoblasts. Cells were incubated for 24 h with standard medium that contained either 25 ng/mL TPA, 1 mmol/L 8-bromo cAMP, or vehicle control. Northern analysis was performed using 3 µg mRNA and probed with 32P labeled cDNA probes. A cyclophilin probe was used for internal control. Human tracheal epithelial cells (hTEC) and COS7 cells were used as a positive or negative control, respectively. Each band was quantified by densitometry, using the PhosphorImager. The blot is a representative of three independent experiments.

 


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  		Figure 4. Ligand-induced production of PGE2 in primary human trophoblasts. Cells were cultured for 24 h in the presence of either 25 ng/mL TPA, 1 mmol/L 8-bromo cAMP, or vehicle control. PGE2 concentration was determined by specific RIA and normalized to cellular protein. Results are presented as mean ± SD and represent three independent experiments, each performed in duplicate. The differences were significant at P < 0.05.

 
cAMP exerts its effects through either PKA-dependent or independent mechanisms (24). To test whether the observed effect of cAMP was mediated by PKA, we cotransfected primary trophoblasts with the PGHS-2 reporter construct, along with an expression vector for the catalytic subunit of PKA (16). As shown in Fig. 5Go, the activity of PGHS-2 promoter was potentiated by 6.6-fold in response to PKA. Coexpression of PKA inhibitor (PKI) caused a 50% reduction in the constitutive activity of PGHS-2 promoter, a 65% reduction in cAMP-induced activation of PGHS-2, and a complete block of PKA effect. These results indicate that cAMP-induced activation of PGHS-2 promoter in trophoblasts is mediated by the PKA.



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  		Figure 5. PKA regulation of PGHS-2 promoter activity in primary human trophoblasts. The PGHS-2 promoter was transfected into primary trophoblasts along with an expression vector for the catalytic subunit of PKA or with its inhibitory peptide, PKI. Cells were incubated for 24 h in the presence of 8-bromo cAMP (1 mmol/L), or vehicle control. Values were normalized to ß-gal activity from a cotransfected RSV ß-gal vector. Results (mean ± SD) are expressed as relative luciferase units (RLU) and represent three independent experiments, each performed in duplicate. The differences induced by PKI were significant at P < 0.05.

 
Aspirin is a nonselective inhibitor of PGHS (3) and also has been shown to inhibits the activity of nuclear factor {kappa} B (25, 26). Because the PGHS-2 promoter contains putative nuclear factor {kappa} B sites (11), we tested whether this promoter is inhibited by aspirin. Aspirin (0.5 mmol/L) had no effect on the constitutive activity of PGHS-2 promoter in primary trophoblasts (Fig. 6Go). In contrast, aspirin diminished the TPA-mediated stimulation of PGHS-2 promoter by 65%. Aspirin also diminished PGHS-2 promoter activation by 8-bromo cAMP, but this effect was not significant. We did not observe any influence of aspirin on PGHS-1 promoter. These results suggest that aspirin is a transcriptional repressor of TPA-stimulated PGHS-2 expression in trophoblast cells.



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  		Figure 6. Aspirin regulation of PGHS-2 promoter activity in primary human trophoblasts. The PGHS-2 promoter was transfected into primary trophoblasts. Cells were incubated for 24 h in the presence of either 1 mmol/L 8-bromo cAMP, 25 ng/mL TPA, or vehicle control, in the presence or absence of aspirin (0.5 mmol/L). Values were normalized to ß-gal activity from a cotransfected RSV ß-gal vector. Results (mean ± SD) are expressed as relative luciferase units (RLU) and represent three independent experiments, each performed in duplicate. *, P < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results indicate that under basal conditions both PGHS-1 and PGHS-2 promoters are active in primary human trophoblasts. The activity of PGHS-2 promoter, but not PGHS-1, is enhanced by either TPA or cAMP. The activation of PGHS-2 promoter correlates with enhanced PGHS-2 expression and activity. We also have confirmed the transcriptional effect of TPA and cAMP in JEG3 cells. This clonal placental cell line is free of other cell types, supporting the notion that the transcriptional regulation of PGHS-2 by TPA or cAMP does not require paracrine influence from nontrophoblastic cells. Although the promoter sequences of PGHS-1 and PGHS-2 used here were previously shown to be highly active in other cell types, we detected a low activity of PGHS-1 promoter, suggesting that trophoblast may be deficient in a transcriptional activator of the PGHS-1 gene. Alternatively, regions located further upstream of our promoter fragments may play a role in the regulation of PGHS-1 and PGHS-2 promoters in placental cells.

Induction of PGHS-2 mRNA was previously demonstrated in response to mitogens, cytokines, inflammatory mediators, and hormones (7). TPA induces PGHS-2 expression in several cell types (22, 27, 28, 29). A direct effect of TPA on the activity of PGHS-2 promoter was demonstrated in human endothelial cells (18). Increased prostanoid production by the placenta has been implicated in the mechanism of labor and in the pathophysiology of preeclampsia (2, 30). Whether the TPA-mediated potentiation of PGHS-2 expression plays a role in these processes is presently unknown. Cyclic AMP-mediated potentiation of PGHS-2 promoter activity was previously shown in human monocytes (19). In human trophoblasts, cAMP regulates syncytium formation, as well as production of CG (20, 21). Because PGHS has been implicated in modulation of cell differentiation, our results may suggest a link between PGHS and trophoblast differentiation. Our results indicate that IL-1ß has no effect on the activity of PGHS-2 promoter in trophoblasts, as shown in rat granulosa cells (31). However, it was previously shown that IL-1ß stimulates PGE2 production by first- and third-trimester human trophoblasts (23). These findings suggest that IL-1ß exerts its effect on prostanoid production through nontranscriptional mechanisms or through additional enzymes that regulate prostanoids synthesis.

We showed that the TPA-mediated potentiation of PGHS-2 promoter activity was diminished by aspirin. Aspirin decreases PG production by inhibiting PGHS activity (3). In addition, aspirin inhibits the transcriptional action of NF{kappa}B, a protein belonging to the rel family of transcription factors (25, 26). PGHS-2 contains NF{kappa}B binding sites in its promoter (11). We therefore speculate that aspirin regulates placental PGHS-2 through inhibition of NF{kappa}B action. Furthermore, the lack of aspirin effect on the constitutive activity of PGHS-2 promoter in human trophoblasts may indicate that NF{kappa}B is not essential for the basal expression of PGHS-2.

We have recently identified an increase in PGHS-2 expression and activity in trophoblasts from preeclamptic patients (Johnson et al, submitted), which may account for the increased thromboxane/prostacyclin ratio. It is plausible that alterations in PGHS-2 expression, mediated through signaling cascades that are activated by TPA or cAMP, contribute to the pathophysiology of preeclampsia. Dissecting the transcriptional regulation of PGHS-2 promoter in trophoblasts from preeclamptic women may shed a new light on the molecular mechanisms underlying preeclampsia.


   Acknowledgments
 
We thank L. H. Wang, R. Maurer, and M. J. Holtzman for plasmids. We also thank Elena Sadovsky for technical assistance.


   Footnotes
 
1 This work was supported in part by NIH Grant R01-HD-29190 (to D.M.N.). Back

Received January 2, 1997.

Accepted March 19, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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