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Biology of Reproduction 60, 541-545 (1999)
©Copyright 1999 Society for the Study of Reproduction, Inc.

Retinoic Acid Stimulates the Expression of 11ß-Hydroxysteroid Dehydrogenase Type 2 in Human Choriocarcinoma JEG-3 Cells1

J. Tremblaya, D.B. Hardya, L.E. Pereiraa, and K. Yang2,a

a The Lawson Research Institute, St. Joseph's Health Centre, Departments of Obstetrics and Gynecology and Physiology, University of Western Ontario, London, Ontario, Canada N6A 4V2


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The syncytiotrophoblasts of the human placenta express high levels of 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), the enzyme responsible for the inactivation of glucocorticoids. It has been proposed that the placental 11ß-HSD2 serves as a barrier to protect the fetus from high levels of maternal cortisol. To examine the hypothesis that nutritional signals regulate the expression of 11ß-HSD2 in placental syncytiotrophoblasts, we investigated the effects of retinoic acids (RAs), the major metabolites of vitamin A, on the expression of 11ß-HSD2 using human choriocarcinoma JEG-3 cells as a model. This trophoblast-like cell line displays a number of functional similarities to the syncytiotrophoblast. Treatment for 24 h with all-trans RA (1–1000 nM) resulted in a dose-dependent increase in 11ß-HSD2 activity with a maximal effect (increase to 3-fold) at 100 nM. The effect of all-trans RA (100 nM) was also time-dependent in that the effect was detectable at 6 h and reached its maximum by 48 h. Similar increases in 11ß-HSD2 activity were observed when the cells were treated with 9-cis RA. Results from semi-quantitative reverse transcription-polymerase chain reaction demonstrated that there was a corresponding increase in 11ß-HSD2 mRNA after RA treatment. Moreover, treatment with actinomycin D (100 ng/ml) abrogated the increase in 11ß-HSD2 mRNA induced by RA, indicating an effect on transcription. In conclusion, the present study has demonstrated for the first time that RA, at physiological concentrations, induces 11ß-HSD2 gene expression and enzyme activity in JEG-3 cells. If this occurs in vivo, the present finding suggests that high expression of 11ß-HSD2 in the human placenta may be maintained, at least in part, by dietary intake of vitamin A.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The placenta plays a pivotal role in the maintenance, development, and termination of pregnancy by profoundly influencing the endocrine milieu of the fetal-maternal unit [1]. Of great and far-reaching physiological significance is the placental metabolism of cortisol [2]. Throughout human pregnancy, the circulating level of cortisol is 3–4 times higher in the mother than that in the fetus [3]. The maintenance of this maternal-fetal cortisol gradient is considered vital to normal fetal development since excessive exposure to glucocorticoids in utero leads to intrauterine growth restriction (IUGR) [4]. It has been suggested that the placental 11ß-hydroxysteroid dehydrogenase (11ß-HSD) is responsible for the maintenance of this gradient by virtue of converting maternal cortisol to its inactive metabolite cortisone [5]. Therefore, the placental 11ß-HSD may serve as a barrier to protect the fetus from higher levels of maternal glucocorticoids [6]. Recently, several lines of evidence have provided strong support for this hypothesis.

First, the human placenta expresses predominantly 11ß-HSD2 rather than 11ß-HSD1 [7, 8]. This is important because fundamental differences exist in the catalytic properties of these two isozymes. 11ß-HSD1 is a low-affinity dehydrogenase (cortisol to cortisone)/reductase (cortisone to cortisol) enzyme, with an apparent affinity for glucocorticoids in the µM range [9, 10]. In intact cells, 11ß-HSD1 functions predominantly as a reductase generating cortisol from cortisone [11]. By contrast, 11ß-HSD2 is a high-affinity unidirectional dehydrogenase enzyme, with an apparent affinity for glucocorticoids in the nM range [12–15]. Therefore, the predominant expression of the high-affinity unidirectional 11ß-HSD2 in the human placenta is consistent with the above hypothesis. Second, 11ß-HSD2 is well positioned within the placenta to fulfill its putative role as a barrier to maternal glucocorticoids since it is localized exclusively to the syncytiotrophoblast, the site of maternal-fetal exchange [16]. Third, in both humans and rats, there is a positive correlation between placental 11ß-HSD2 activity and birth weight [7, 17]. Fourth, placental 11ß-HSD2 activity is attenuated in pregnancies complicated with IUGR [18]. Moreover, IUGR is a characteristic feature of apparent mineralocorticoid excess [19], a syndrome resulting from 11ß-HSD2 deficiency [20].

However, the factors maintaining high 11ß-HSD2 expression in human placental syncytiotrophoblasts are poorly understood. A number of elegant studies in the baboon by Pepe, Albrecht, and coworkers have provided convincing evidence that estrogen increases the placental 11ß-HSD dehydrogenase activity both in vivo and in vitro [21–23]. In a more recent study using cultured human placental syncytiotrophoblasts, Sun and coworkers demonstrated an inhibition of 11ß-HSD2 activity by estrogen [24]. These contrasting effects of estrogen in the baboon and human may be attributed to species differences in the response of placental 11ß-HSD2 to estrogen. Alternatively, the estrogen-induced increase in the baboon placental 11ß-HSD dehydrogenase activity may be associated with 11ß-HSD1 as this isozyme is expressed in the baboon placental syncytiotrophoblasts [25].

During mammalian pregnancy, vitamin A (retinol) and its biologically active derivatives (retinoids), most notably retinoic acids (RAs), exert profound effects on fetal development and placental function [26–28]. To investigate the role of RAs in the metabolism of glucocorticoids within the placenta, we examined the effects of RAs on the expression of 11ß-HSD2 using human choriocarcinoma JEG-3 cells as a model. This trophoblast-like cell line expresses only the 11ß-HSD2 isozyme [29] and has retained the capacity to produce progesterone, hCG, and other placental hormones and enzymes, and therefore has been used extensively as a model for placental syncytiotrophoblasts [30–32]. In this study, we used all-trans RA and 9-cis RA, the two major forms of retinoic acid found in the human body [33]. Our results demonstrate that both all-trans RA and 9-cis RA are potent stimulators of 11ß-HSD2 enzyme activity and mRNA expression in JEG-3 cells.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Reagents and Supplies

[1,2,6,7-3H(N)]Cortisol (80 Ci/mmol) was purchased from DuPont Canada Inc. (Markham, ON, Canada). Nonradioactive steroids were obtained from Steraloids Inc. (Wilton, NH). Forskolin and actinomycin D were purchased from Sigma Chemicals (St. Louis, MO). Polyester-backed thin-layer chromatography (TLC) plates were obtained from Fisher Scientific Ltd. (Unionville, ON, Canada). All solvents used were OmniSolv grade from BDH Inc. (Toronto, ON, Canada). General molecular biology reagents were from Gibco BRL (Burlington, ON, Canada) or Pharmacia Canada Inc. (Baie D'Urfe, PQ, Canada). The JEG-3 cell line was purchased from the American Type Culture Collection (Rockville, MD). Cell culture supplies were obtained from Gibco BRL or Fisher Scientific. All-trans retinoic acid and 9-cis retinoic acid were generously provided by Dr. T. Drysdale, Lawson Research Institute (London, ON, Canada).

Cell Culture and Treatments

JEG-3 cells were cultured in Minimum Essential Medium Eagle supplemented with 10% FBS, nonessential amino acids, sodium pyruvate, and penicillin/streptomycin. Cells were maintained in T-25 Corning flasks (Corning, NY) at 37ÅC in a 95% air:5% CO2 humidified incubator. The medium was changed every other day. The cells were passed as required. To study the effects of RAs on 11ß-HSD2 activity, cells were passed onto 12-well Corning plates and cultured to confluence. The cells were then cultured in serum-free medium for 24 h before treatment, and all the treatments were carried out under serum-free conditions. Cells in triplicate wells were exposed to a given dose of retinoic acid for 24 h or as stated otherwise. Controls (also in triplicate) were treated similarly but without the addition of retinoic acid. For 11ß-HSD2 mRNA analysis, cells were subjected to culture and treatment conditions identical to those described above except that they were maintained in T-25 flasks. Moreover, forskolin (10 µM), a known stimulator of 11ß-HSD2 mRNA in JEG-3 cells [29], was added to the cells for 24 h to serve as a positive control.

Assay of 11ß-HSD2 Activity—Radiometric Conversion Assay

At the end of treatment, the cells were washed 3 times in serum-free medium. The level of 11ß-HSD2 activity in intact cells was determined by measuring the rate of cortisol to cortisone conversion, as described previously [24, 34]. Briefly, the cells were incubated for 4 h at 37ÅC in serum-free medium containing approximately 100 000 cpm [3H]cortisol and 10 nM unlabeled cortisol (preliminary studies indicated that the rate of reaction from 1 to 12 h was linear with time at this cell density and using this substrate concentration). At the end of incubation, the medium was collected, and steroids were extracted. The extracts were dried, and the residues were resuspended. A fraction of the resuspension was spotted on a TLC plate, which was developed in chloroform/methanol (9:1, v:v). The bands containing the labeled cortisol and cortisone were identified by UV light of the cold carriers, cut out into scintillation vials, and counted in Scintisafe Econol 1 (Fisher Scientific, Toronto, ON, Canada). The rate of cortisol to cortisone conversion was calculated from the specific activity of the labeled cortisol and the radioactivity of cortisone, the blank values (defined as the amount of conversion in the absence of cells) were subtracted, and results were expressed as the amount of cortisone (picomoles) formed per 4 hours per well. Results are shown as mean ± SEM. One-way ANOVA followed by Dunnett's test was used to determine statistical differences, and significance was set at p < 0.05.

Analysis of 11ß-HSD2 mRNA—Semi-Quantitative Reverse Transcription (RT)-Polymerase Chain Reaction (PCR)

Total RNA was extracted from cultured cells using an RNeasy kit (Qiagen Inc., Mississauga, ON, Canada) according to the manufacturer's instructions. Before use, the RNA samples (1–2 µg) were checked by agarose gel electrophoresis in the presence of formaldehyde, and the integrity of the RNA was assessed by the presence of two sharp bands representing 28S and 18S rRNA after staining with ethidium bromide. One microgram of total RNA was reverse-transcribed using a standard oligo(dT) primer in a total volume of 20 µl. An aliquot (2 µl) of the RT reaction products was then subjected to a standard PCR (95ÅC, 55 sec; 55ÅC, 55 sec; 72ÅC, 1 min; 32 cycles) using sequence-specific primers (forward primer, 5'-AGTAGTTGCTGATGCGGA; reverse primer, 5'-ACCACAGTCCATGCCATCAC), which correspond to nucleotides 624–641 and 1004–1021, respectively, in the published human 11ß-HSD2 cDNA [13]. Glyceraldehyde phosphate dehydrogenase (GAPDH) was used as a control. The same PCR conditions were used for GAPDH except that a cycle number of 25 instead of 32 was used. The primers for GAPDH (forward primer, 5'-ACCACAGTCCATGCCATCAC; reverse primer, 5'-TCCACCACCCTGTTGCTGTA) were obtained from Clontech Laboratories Inc. (Palo Alto, CA), and they correspond to nucleotides 586–605 and 1018–1037, respectively, in the published human GAPDH cDNA [35]. To verify the RT-PCR products and to assess the relative abundance of 11ß-HSD2 mRNA, a fraction of the RT-PCR products was then subjected to a standard Southern blot analysis, using 32P-human 11ß-HSD2 cDNA and 32P-human GAPDH cDNA as probes. Each experiment was repeated, and a representative figure from each analysis is shown.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effects of RA on 11ß-HSD2 Activity

To study the effects of RA on 11ß-HSD2 activity in JEG-3 cells, the cells were treated with all-trans RA (100 nM) for different times (6, 12, 24, and 48 h). Significant stimulation of 11ß-HSD2 activity was evident at 12 h (p < 0.05), and by 48 h (p < 0.01) near-maximal stimulation (approximately 400% of the control) was found (Fig. 1). When cells were exposed to different concentrations of all-trans RA, ranging from 1.0 to 1000 nM, for 24 h, there was a dose-dependent increase in the level of 11ß-HSD2 activity following the RA treatment with the maximal effect at 100 nM (increase to approximately 3-fold; p < 0.01; Fig. 2). Similar dose-dependent increases in 11ß-HSD2 activity were observed when cells were treated with 9-cis RA (data not shown).



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  		FIG. 1. Induction of 11ß-HSD2 activity by all-trans RA: time course. Cells were incubated with 100 nM all-trans RA in the absence of serum for the indicated times. At the end of treatment, the level of 11ß-HSD2 activity in intact cells was determined by a radiometric conversion assay, as described in the Materials and Methods. Bars represent the mean ± SEM of three independent experiments, each performed in triplicate. * p < 0.05, and ** p < 0.01 when compared with the control.



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  		FIG. 2. Induction of 11ß-HSD2 activity by all-trans RA: dose-response curve. Cells were incubated for 24 h with the indicated concentrations of all-trans RA in the absence of serum. At the end of treatment, the level of 11ß-HSD2 activity in intact cells was determined by a radiometric conversion assay, as described in the Materials and Methods. Bars represent the mean ± SEM of three independent experiments, each performed in triplicate. * p < 0.05, and ** p < 0.01 when compared with the control.

Effects of RA on 11ß-HSD2 mRNA

In order to determine whether increases in 11ß-HSD2 activity after RA treatment were associated with changes in 11ß-HSD2 mRNA, the relative level of 11ß-HSD2 mRNA in JEG-3 cells was assessed by a semiquantitative RT-PCR analysis. Treatment of JEG-3 cells with all-trans RA or 9-cis RA (100 nM) resulted in a corresponding increase in the level of 11ß-HSD2 mRNA. As expected, the addition of forskolin to the cells caused an increase in 11ß-HSD2 mRNA (Fig. 3A).



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  		FIG. 3. Induction of 11ß-HSD2 mRNA by all-trans RA and 9-cis RA. Autoradiographs of the semi-quantitative RT-PCR analysis of 11ß-HSD2 mRNA in JEG-3 cells after treatment with RA in the absence (A) and presence (B) of actinomycin D. Cells were treated for 24 h in serum-free medium with 10 µM forskolin (positive control), 100 nM all-trans RA, or 100 nM 9-cis RA in the presence and absence of 100 ng/ml actinomycin D. At the end of treatment, total cellular RNA was extracted and subjected to a semi-quantitative RT-PCR, followed by Southern blotting, as described in the Materials and Methods.

To examine the mechanisms underlying the increases in 11ß-HSD2 mRNA following RA treatment, the cells were coincubated with all-trans RA and actinomycin-D, an inhibitor of transcription. It was found that the addition of actinomycin-D abolished the RA-induced increases in 11ß-HSD2 mRNA (Fig. 3B).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the study reported here, we demonstrated that both all-trans RA and 9-cis RA stimulate the expression of 11ß-HSD2 activity and mRNA in JEG-3 cells, suggesting that dietary intake of vitamin A may play an important role in maintaining high expression of 11ß-HSD2 in the placenta.

We examined the nature of the regulation of 11ß-HSD2 by RA in JEG-3 cells. The two major physiological forms of RA stimulated 11ß-HSD2 activity similarly, in a dose- and time-dependent manner. Moreover, the RA-induced 11ß-HSD2 activity was caused by an increase in the steady-state level of 11ß-HSD2 mRNA since a corresponding increase in 11ß-HSD2 mRNA, as assessed by a semiquantitative RT-PCR analysis, was observed after RA treatment. Changes in mRNA accumulation can be attributed to alterations in the rate of transcription and/or in mRNA stability. In order to investigate the underlying mechanisms of the increased 11ß-HSD2 mRNA by RA, JEG-3 cells were cotreated with actinomycin D, an inhibitor of transcription. The rationale was that if the effects of RA were mediated at the level of 11ß-HSD2 gene transcription, the addition of actinomycin D should abolish the RA-induced increase in 11ß-HSD2 mRNA. The results demonstrate that treatment with actinomycin D abrogated the increase in 11ß-HSD2 mRNA that followed RA treatment. Thus, the effects of RA on 11ß-HSD2 in JEG-3 cells are mediated, at least in part, through changes in the rate of 11ß-HSD2 gene transcription.

RAs exert their effects via 2 distinct families of nuclear receptors, the retinoic acid and retinoid X receptors (RARs and RXRs). Each family of receptors consists of 3 subtypes, namely, RAR-{alpha}, -ß, and -{gamma} and RXR-{alpha}, -ß, and -{gamma}. RARs bind and respond to either all-trans RA, or 9-cis RA, while RXRs are activated exclusively by 9-cis RA. These receptors are ligand-inducible and function as dimeric trans-regulators that modulate transcription of target genes by interacting with cis-acting RA response elements (RAREs) [33]. In the present study, all-trans RA was effective in stimulating 11ß-HSD2 expression at a concentration of 10 nM, which is within the physiological level in vivo and is consistent with that required to activate RARs [36]. Likewise, 9-cis RA was also effective in this regard at 10 nM, suggesting that the effects of 9-cis RA on 11ß-HSD2 are mediated through RXRs and/or RARs. Indeed, JEG-3 cells have been shown to express high levels of RXR-{alpha} but not RAR-ß [37]. It remains possible that this cell line also expresses RAR-{alpha} since both RAR-{alpha} and RXR-{alpha} have been identified recently in human placental syncytiotrophoblasts [38]. Therefore, it is plausible that heterodimers of RAR-{alpha} and RXR-{alpha} may interact directly with DNA response elements (RAREs) in the 11ß-HSD2 promoter region to regulate the expression of 11ß-HSD2 in JEG-3 cells. The characterization of such elements is currently in progress.

It is noteworthy that dexamethasone down-regulates the expression of cellular retinol-binding protein, a potential mediator of vitamin A action, in the rat [39]. This finding, coupled with our present data, suggests a dynamic relationship between glucocorticoid and RA in maintaining proper embryonic development.

Previous studies using JEG-3 cells have shown that both forskolin and dibutyryl cAMP stimulate the expression of 11ß-HSD2 mRNA and activity [29]. Furthermore, progesterone is a potent inhibitor of 11ß-HSD2 activity in JEG-3 cells [40]. In cultured human placental trophoblasts, it has been demonstrated that nitric oxide, estrogen, and progesterone selectively down-regulate the expression of 11ß-HSD2 [24, 34]. In the present study, we have demonstrated that RAs are potent stimulators of 11ß-HSD2 expression in JEG-3 cells. Collectively, these findings indicate that the expression of 11ß-HSD2 in the placenta is controlled not only by systemic and local hormones/factors but also by nutritional signals, such as RAs. The elucidation of the underlying mechanisms and interactions between these physiological regulators will undoubtedly provide new insight into our understanding of fetal-placental function and development.


   FOOTNOTES
 
1 This work was supported by the Canadian MRC (Grant MT-12100 to K.Y.). K.Y. is an Ontario Ministry of Health Career Scientist. Back

2 Correspondence: K. Yang, Lawson Research Institute, 268 Grosvenor Street, London, ON, Canada N6A 4V2. FAX: 519 646 6110; kyang{at}julian.uwo.ca Back

Accepted: October 5, 1998.

Received: July 4, 1998.


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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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