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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 4 1737-1741
Copyright © 2003 by The Endocrine Society

Regulation of 15-Hydroxy Prostaglandin Dehydrogenase by Corticotrophin-Releasing Hormone through a Calcium-Dependent Pathway in Human Chorion Trophoblast Cells

K. J. McKeown and J. R. G. Challis

Canadian Institutes of Health Research Group in Fetal and Neonatal Health and Development, Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Canada M5S 1A8

Address all correspondence and requests for reprints to: Kevin McKeown, M.D., Department of Physiology Medical Sciences Building, Room 3344, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada. E-mail: kevin.mckeown{at}utoronto.ca.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Prostaglandins (PGs) play a crucial role in mediating parturition events, and their synthesis and metabolism are regulated by PG H synthase and 15-hydroxy-PG dehydrogenase (PGDH), respectively. Within the chorion tissue, it is the actions of PGDH that predominate. Throughout gestation, the fetal membranes secrete increasing amounts of CRH. We hypothesized that CRH, produced locally in the chorion, could act to modulate PGDH activity throughout gestation. To investigate this, we obtained Percoll-purified human chorion and placental trophoblast cells from uncomplicated term pregnancies and cultured them for 72 h. Activity of PGDH was assessed by incubation (4 h) with PGF2{alpha} (282 nM) and measurement of conversion to 13,14-dihydro-15-keto PG F2{alpha}. Dose-response curves were constructed for the chorion cell cultures with CRH or 8-bromo-cAMP. To investigate the role of CRH and calcium, cells were treated with either astressin, a CRH antibody, BAPTA, or EGTA. CRH (0–1 µM) had no effect on PGDH activity; however, cells treated with astressin (10 µM), with or without exogenous CRH (1 µM), and cells treated with a CRH antibody showed a significant decrease in PGDH activity. 8-Bromo-cAMP (0–1 mM) had no effect on 13,14-dihydro-15-keto PG F2{alpha} output in chorion trophoblast cells but significantly decreased output from placental trophoblast cells. Cells treated with either BAPTA-AM or EGTA had significantly reduced PGDH activity; and, at intermediate concentrations of chelator, exogenous CRH restored PGDH activity. We suggest that, in chorion trophoblast cells, endogenously produced CRH exerts a tonic stimulatory effect on PGDH activity and may help maintain a metabolic barrier, preventing the transfer of bioactive PGs from the chorioamnion to the myometrium.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PROSTAGLANDINS (PGs) HAVE been shown to play a crucial role in the labor process by stimulating uterine contractility and causing ripening of the cervix (1, 2). PGs have also been shown to play an important role in up-regulation of the fetal hypothalamic-pituitary-adrenal axis (3), membrane rupture (4), and the maintenance of uterine and placental blood flow. Throughout gestation, the amnion and chorion are major producers of PGs (in particular, PGE2 and PGF2a) (5, 6). PGs are formed from arachadonic acid released from membranes stores by the action of PG H synthase (PGHS) (7, 8). Metabolism of these PGs proceeds through the activity of the enzyme NAD-dependent 15-hydroxy-PG dehydrogenase (PGDH) (9, 10). PGDH catalyzes the reversible oxidation of the PGs of the E and F series to form 15-keto biologically inactive metabolites (11).

In the fetal membranes, it has been found that PGHS and PGDH are present in both the amnion and chorion (12, 13). Although both enzymes are present, many investigators have shown that PGDH action predominates in the human chorion tissue (14, 15). It has been suggested that the presence of this enzyme in the chorion could act as a metabolic barrier to block the transfer of PGs produced by the amnion and chorion cells throughout gestation (16, 17). The actions of PGDH would prevent any bioactive PGs from crossing to the decidua and myometrium, where they could cause early activation of uterine contractility.

At the onset of term and preterm labor, there is an increase in the levels of PGHS-II along with a large increase in the amount of active PGs (18). Along with the increase in PGs, there is also an increase in other substances, such as cortisol and CRH (19). The fetal membranes, including the chorion trophoblast cells, have been shown to express increased levels of CRH at term and preterm labor (20). Located within the chorion are CRH-R1{alpha}, CRH-R2ß, and variants CRH-R1c and CRH-R1d receptors, which are G protein-coupled membrane receptors that, in many other tissues, are capable of activating adenylate cyclase and producing increased intracellular levels of cAMP (21, 22). In a previous study (23), it was shown that, within the placental trophoblast cells, PGDH activity could be decreased by increased concentrations of cAMP. In a recent study by Hillhouse and colleagues (24), it was demonstrated that, within the human fetal membranes, the CRH receptors may be coupled to the {alpha}-subunit of Gq and can also activate Go. The Gq subunit can then go on to activate PLCß and activate an inositol triphosphate (IP3) pathway, whereas Go activation can couple directly to calcium channels and modulate calcium influx (25). Therefore, we hypothesized that CRH produced locally in the chorion trophoblast cells could act to modulate PGDH activity throughout gestation and at labor, modulating the bioactive levels of PGs. In the present study, we determined the effects of CRH on PGDH activity and then investigated whether these effects on activity could have occurred through a cAMP- or Ca2+-dependent pathway.


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

Human choriodecidual tissue (n = 12 patients) and placentae (n = 4 patients) were obtained from uncomplicated normal term pregnancies, after elective cesarean section, using protocols approved by Mount Sinai Hospital and the University of Toronto. Trophoblast cells from choriodecidual tissue and placental cotyledons were isolated and cultured using a modification of the technique described by Kliman et al. (26, 27, 28), as published previously. Briefly, approximately 60 g of cotyledon tissue were removed randomly from the maternal side of the placenta, pooled, and digested with 0.125% trypsin (Sigma, St. Louis, MO) and 0.02% deoxyribonuclease-I (Sigma) in DMEM (Life Technologies, Inc., Grand Island, NY) containing 0.1% BSA, 0.005% gentamicin, and 0.01% streptomycin, three times for 30 min each time. The chorion with adherent decidua was peeled off amnion and digested, three times for 60 min each time, using the same digestion medium with the addition of 0.2% collagenase (Sigma). The dispersed choriodecidual or placental cells were filtered with a 200-µm nylon gauze and loaded onto a discontinuous Percoll (Sigma) gradient (5–70% in 5% steps of 3 ml each), then centrifuged at 37 C and 1200 x g for 20 min to separate different cell types. Cytotrophoblast cells between the density markers of 1.049 and 1.062 g/ml were collected and plated in 24-well plates (Corning, Inc. Costar Corp., Cambridge, MA), at a density of 106 cells/ml per well, in DMEM culture medium containing 10% FCS (Life Technologies, Inc.). The cells were cultured for 3 d, at 37 C in 5% CO2-95% air, before experimentation.

Tissue culture analyses

Trophoblast cells were grown for 3 d and then incubated for 24 h in serum-free fresh DMEM that contained one of the following treatments: CRH (0–1000 nM); astressin (10 µM); an antagonist specific for the CRH receptor subtypes, in the presence or absence of exogenous CRH (1 µM). Chorion trophoblast cells were also treated with a polyclonal rabbit human CRH antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) to remove CRH produced by the cells from the media. To examine the role of cAMP on PGDH activity in chorion, cells were treated with either Forskolin (0–1000 nM), capable of activating endogenous adenylate cyclase, or 8-bromo-cAMP (0–1 mM). To examine the role of calcium in the modulation of PGDH expression and activity, chorion cells were treated with BAPTA-AM (1–50 µM), an intracellular calcium chelator, or EGTA in the presence or absence of exogenous CRH (1 µM). Control cultures were maintained without additives, and each treatment was performed in triplicate for each preparation of cells. After 24 h, the medium was replaced with fresh medium containing PGF2{alpha} (282 nM), and cells were incubated for 4 h (29). The medium was then collected and stored at -80 C for later assessment of PGDH activity.

PGDH activity was determined by RIA to measure the concentration of 13,14-dihydro-15-keto PGF2{alpha} (PGFM), the stable metabolite of PGF2{alpha}, in the culture medium, as described previously (30). The intra-assay and interassay coefficients of variation were 4.5% and 8.1%, respectively. CRH was measured with the use of a commercial enzyme immunoassay assay kit, and the calculated control value was within 2% of the defined concentration (Phoenix Pharmaceuticals, Inc., Belmont, CA).

At the end of each experiment, representative wells of cells were fixed and immunostained for cytokeratin and vimentin using primary antibodies (DAKO Corp., Santa Barbara, CA) at 1:1000 and 1:100 dilutions, respectively, to assess cell purity (26). Other cultures were stained for PGDH, with a polyclonal primary antibody raised against purified human placental type 1 PGDH (Cayman Laboratories, Ann Arbor, MI).

Statistical analysis

Effects of treatments on PGDH activity were assessed, using one-way ANOVA for repeated measures on the original data, followed by post hoc analysis by Tukey’s correction with significance set at P value less than 0.05. For illustrative purposes, the results are presented as the mean percent control ± SEM.


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

At the end of the culture period, chorion trophoblast cells were present as clumps of cells or as single cells. Placenta trophoblast cells tended to form aggregates, thought to correspond to syncytium formation in vivo. These cells were predominately cytokeratin-positive (>90%) and vimentin-negative. The chorion and placenta trophoblast cell cultures stained positive for immunoreactive PGDH.

Effects of CRH on PGDH activity

CRH showed no effect on PGDH enzyme activity in chorion trophoblast cells when treated at a maximum concentration of 1 µM (Fig. 1AGo). To determine whether these cells were producing endogenous CRH, we measured the level of CRH in the culture media of control cells and found 167.5 (35 pM) ± 26.6 pg/ml after a 4 h incubation period. To block effects of endogenous CRH, cells were treated with increasing concentrations of the CRH receptor antagonist astressin, which, at 10 µM, resulted in a significant decrease in PGDH activity after a 24-h treatment period (Fig. 1AGo). Cells that were treated with astressin (10 µM) and exogenous CRH (1 µM) showed a significant decrease in PGDH activity, compared with control treatment, that was not significantly different from cells treated with astressin alone (Fig. 1AGo). Treatment of cells with a CRH antibody significantly decreased PGDH activity, to a maximum of 77.9 ± 2.3% of control, at an antibody concentration of 2.5 µg (Fig. 1BGo). Cells treated with rabbit IgG control (2.5 µg) had PGDH activity that was not significantly different from that of control cultures (Fig. 1BGo).



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  		Figure 1. A, Effects of astressin and CRH on PGDH activity in chorion trophoblast cells. Values are presented as mean percent control ± SEM for n = 4 cultures. Statistical analysis was performed using a one-way ANOVA for repeated measures on the original data, followed by post hoc analysis using Tukey’s test. PGDH activity was not significantly effected by CRH (1 µM), but PGDH activity was significantly decreased when cells were treated with Astressin (10 µM) in the absence or presence of exogenous CRH (1 µM). Values with different superscripts (A and B) are significantly different from each other (P < 0.05). B, Dose response for CRH-Ab on PGDH activity in chorion trophoblast cells. Values are presented as mean percent control ± SEM for n = 4 cultures. Statistical analysis was performed using a one-way ANOVA for repeated measures on the original data, followed by post hoc analysis using Tukey’s test. PGDH activity was significantly decreased by the CRH-Ab at a concentration of 1:500 to 1:50. Cells treated with control IgG (2.5 µg, 1:50) had no significant effect on PGDH activity. Values with different superscripts (a, b, c, and d) are significantly different from each other (P < 0.05).

 
Effects of forskolin and 8-bromo-cAMP on PGDH activity

Forskolin treatment of the chorion trophoblast cells showed no significant effect on PGDH activity when treated at a maximum concentration of 1 µM (data not shown). PGDH activity also showed no significant change when chorion cells were treated with 8-bromo-cAMP up to a maximum concentration of 1 mM (Fig. 2Go). However, PGDH activity in placenta trophoblast cells was significantly decreased with 8-bromo-cAMP (1 mM) in accordance with the previous study of Lennon et al. (23) (Fig. 2Go).



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  		Figure 2. Effects of 8-bromo-cAMP on PGDH activity in chorion trophoblast and placenta trophoblast cells. Values are presented as mean percent control ± SEM for n = 4 cultures (placenta, 0.1-mM dose, n = 3). Statistical analysis was performed using a one-way ANOVA for repeated measures on the original data, followed by post hoc analysis using Tukey’s test. There was no significant effect of 8-bromo-cAMP on PGDH activity in chorion trophoblast cells, although PGDH activity in placenta trophoblast cells was significantly decreased by 8-bromo-cAMP (1 mM). *, Significantly different (P < 0.05).

 
Effect of BAPTA-AM and EGTA on PGDH activity

Treatment of chorion cell cultures with BAPTA (1–50 µM) significantly decreased PGDH activity, at a concentration of 10 and 50 µM, to 54.1 ± 8.2 and 20.1 ± 7.7% of control values, respectively (Fig. 3Go). CRH (1 µM) in the presence of BAPTA-AM (10 µM) restored PGDH activity to control levels and significantly increased activity, compared with the cells that were treated with BAPTA (10 µM) alone (Fig. 3Go). Chorion trophoblast cells treated with EGTA at a concentration of 1 mM had significantly decreased PGDH activity, to approximately 40% of the control value (Fig. 4Go). Addition of exogenous CRH (1 µM) reversed the decrease in PGDH activity caused by the addition of EGTA, to a value that was increased significantly, compared with cells treated with EGTA alone (Fig. 4Go).



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  		Figure 3. Effect of BAPTA-AM treatment on PGDH activity in chorion trophoblast cells. Values are presented as mean percent control ± SEM for n = 4 cultures. Statistical analysis was performed using a one-way ANOVA for repeated measures on the original data, followed by post hoc analysis using Tukey’s test. BAPTA-AM significantly decreased PGDH activity in chorion trophoblast cells at a concentration of 10 and 50 µM. The decreased PGDH activity was attenuated when treated with BAPTA-AM (10 µM) and exogenous CRH (1 µM); and it was significantly increased, compared with cells treated with BAPTA-AM (10 µM) alone. Addition of exogenous CRH (1 µM) could not restore PGDH activity in chorion cells coincubated with BAPTA-AM (50 µM). Values with different superscripts (a, b, and c) are significantly different from each other (P < 0.05).

 


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  		Figure 4. Effect of EGTA treatment on PGDH activity in chorion trophoblast cells. Values are presented as mean percent control ± SEM for n = 4 cultures. Statistical analysis was performed using a one-way ANOVA for repeated measures on original data, followed by post hoc analysis using Tukey’s test. EGTA significantly decreased PGDH activity at a concentration of 1 µM. Addition of exogenous CRH (1 µM) significantly increased PGDH activity, compared with cells treated with EGTA alone. Values with different superscripts (a and b) are significantly different from each other (P < 0.05).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we have demonstrated that, when CRH receptors were blocked in chorion cells with the administration of a specific CRH receptor antagonist, there was a significant decrease in PGDH activity. The addition of a CRH antibody to the chorion trophoblast cultures significantly decreased PGDH activity in a dose-dependent pattern. We also found that PGDH activity was down-regulated in placenta trophoblast cells by 8-bromo-cAMP; however, with the same concentration of cAMP, PGDH in the chorion trophoblast cells was unaffected. PGDH activity was significantly decreased when either intracellular or extracellular Ca2+ was chelated, and this decrease could be reversed by the addition of exogenous CRH. These data support the hypothesis that CRH may act through a calcium-dependent pathway to stimulate or maintain PGDH activity in chorion trophoblast cells throughout gestation and that regulation of this enzyme differs between the chorion and placenta trophoblast cells.

In this study, we have not determined whether the treatment effects were only at the level of protein or whether these were also changes in the PGDH mRNA. However, we have demonstrated clearly an effect on the enzyme’s levels of functional activity. The PGDH gene promoter region contains many important regulatory subunits that could allow CRH to modulate gene expression through a Ca2+-dependent pathway. In a recent study, the 3.5 kb of the 5' flanking sequence of the human PGDH gene was characterized and found to contain a cAMP-responsive element-binding protein (CREB), Ets, and activating protein-1 (31). CREB activation can occur through two major pathways, either by a cAMP signaling pathway, or a calcium-calmodulin-dependent protein kinase pathway (32). Therefore, there are several potential sites with which that a Ca2+-dependent pathway could interact to modulate the mRNA expression of PGDH in chorion.

Bioactive PGs have been implicated as integral uterotonins in the labor process, and two important enzymes, PGHS-2 and PGDH, control their synthesis and metabolism, respectively (6, 33). PGDH located within the chorion has been suggested to play a crucial role in maintaining a metabolic barrier to bioactive PGs, preventing PGs from crossing into the decidua and myometrium, where they could cause early uterine activation (13, 17). In addition to expressing these enzymes, the human placenta and fetal membranes secrete increased amounts of CRH as gestation progresses (34). During the final 3 wk of gestation, the CRH-binding protein concentration falls, and there is a rapid increase in the amount of CRH released by the fetal membranes, which results in a large rise in bioactive CRH concentrations (35). The chorion trophoblast cells have been shown to contain the CRH-R1{alpha}, CRH-R2ß, and variants CRH-R1c and CRH-R1d receptors (21, 36). These CRH receptors are composed of seven transmembrane-spanning domains and are G protein-coupled receptors (37). The competitive antagonist astressin has been shown to block both CRH-R1 and R2 receptors (38). We found that blocking these receptors in chorion cells resulted in a significant decrease in PGDH activity. In the present experiments, we used an amount of astressin previously reported by Ha et al. (39) to block CRH effects in the chorion; however, in the current study, we were unable to determine which receptor subtype was responsible for these effects on PGDH activity. Our results do suggest, however, that CRH may act in an autocrine/paracrine fashion and play an important role in local regulation of PGDH activity throughout gestation and at labor.

Regional distribution of CRH receptors and different second-messenger pathways may allow for regional and temporal differences in CRH actions in various tissues. This thesis is supported, in our study, by the results showing down-regulation of PGDH in placental trophoblast by 8-bromo-cAMP, without effect of cAMP in the chorion trophoblast cells (23). CRH has been shown to stimulate adenylate cyclase activity in myometrium and to increase cAMP, which helps to maintain uterine quiescence (40). This local regulation could occur because of different CRH receptor subtypes or second-messenger pathways being used. PGs in the fetal membranes may help to remodel the extracellular matrix and prepare the membranes for rupture (41); however, it would be desirable that these PGs do not cross into the myometrium until the fetus is mature. CRH has been shown to stimulate PGHS-2 (and hence, PG output) in fetal membranes (42) and also to stimulate PGDH in the chorion, thereby ensuring that the PG action remain local. A high level of PGDH activity in the chorion, throughout gestation, limits peripheral effects of PGs and ensures that early uterine activation does not occur.

In this study, we have demonstrated that, when Ca2+ was depleted from chorion cells, there was a decrease in PGDH activity. In the fetal membranes, it has been shown that CRH acts through its receptors, to activate an IP3 pathway, which could increase intracellular levels of Ca2+ through the mobilization of intracellular calcium stores (24, 43). In addition to this, CRH can also activate a Go subunit, which may then act directly on Ca2+ channels and increase influx (24). In cultured rat astrocytes, CRH increased Ca2+ influx, and this increase was independent of cAMP formation, indicating that CRH can act directly on channels, to allow extracellular calcium to enter the cell (44). CRH produced locally may then be able to mobilize a large calcium response through both the release of intracellular stores and an increase in the influx from outside the cell, through membrane channels. Our ability to stimulate PGDH activity with CRH in the presence of intermediate amounts of extra BAPTA-AM or EGTA may reflect the potential utilization of calcium from either intracellular or extracellular sources, or may simply indicate that the amount of intermediate chelator is saturated under the conditions employed.

In some situations of impending preterm labor, CRH concentrations in maternal plasma are elevated significantly (45). We speculate that this rise in CRH contributes locally to maintaining chorionic PGDH activity and is part of a mechanism to prevent myometrial activation (46). In some cases of idiopathic preterm labor, chorion PGDH activity is significantly decreased (13), and this may allow inappropriate transfer of bioactive PGs to the myometrium and decidua. It is possible that this results from a deficiency in the CRH signaling pathway and an inability of CRH to stimulate PGDH in chorion trophoblast cells.


   Acknowledgments
 
We thank Dr. L. Myatt for his generous donation of the PGFM antibody used in this study.


   Footnotes
 
Abbreviations: CREB, cAMP-responsive element-binding protein; PG, prostaglandin; PGDH, 15-hydroxy-PG dehydrogenase; PGFM, 13,14-dihydro-15-keto PG F2{alpha}; PGHS, PG H synthase.

Received August 28, 2002.

Accepted January 3, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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