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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 8 3774-3778
Copyright © 2002 by The Endocrine Society

Original Article

Estrogen Represses whereas the Estrogen-Antagonist ICI 182780 Stimulates Placental CRH Gene Expression

Xin Ni, Richard C. Nicholson, Bruce R. King, Eng-Cheng Chan, Mark A. Read and Roger Smith

Mothers and Babies Research Center (R.C.N., B.R.K., E.-C.C., M.A.R., R.S.), Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales 2310, Australia; and Department of Physiology (X.N.), Second Military Medical University, Shanghai 200433, People’s Republic of China

Address all correspondence and requests for reprints to: Roger Smith, Locked Bag 1, Hunter Region Mail Center, New South Wales 2310, Australia. E-mail: . mdrsm{at}mail.newcastle.edu.au

Abstract

CRH and estrogens, produced by placental trophoblasts, have been suggested to play pivotal roles in the control of human parturition. Estrogen has been shown to affect hypothalamic CRH expression. Therefore, we evaluated 17ß-estradiol (E2) in the regulation of CRH gene expression in placental cells. E2 inhibited CRH mRNA expression in a dose-dependent manner, which paralleled the decrease in CRH protein levels in culture media. A complete estrogen receptor (ER) antagonist, ICI 182780, not only blocked repression of CRH mRNA levels by E2, but up-regulated CRH mRNA and protein synthesis. An ER{alpha}-mixed agonist/antagonist and ERß antagonist, 4-hydroxytamoxifen, also down-regulated CRH gene expression. Using quantitative RT-PCR, we found that placental trophoblasts express predominantly the ER{alpha} form of the receptor. Transient transfection assays conducted in the choriocarcinoma cell line JEG-3 demonstrated that E2 repressed CRH promoter activity, whereas the antagonist ICI 182780 up-regulated CRH promoter activity when ER{alpha} was cotransfected. These studies demonstrate that E2 represses placental CRH gene expression through an ER{alpha}- mediated mechanism. Estrogen may therefore modulate placental CRH production, influencing the rate of rise of maternal plasma CRH concentrations and potentially the length of gestation.

CRH, FIRST IDENTIFIED in the hypothalamus, is also produced by the human placenta (1, 2). During human pregnancy, placental syncytiotrophoblasts secrete large amounts of CRH into the maternal and fetal circulations. Synthesis of CRH in the placenta increases exponentially with advancing gestation, and this increase is mirrored by an exponential increase in CRH concentration in maternal plasma (3, 4, 5). Several studies strongly suggest that placental CRH production is linked to the length of human pregnancy and abnormally elevated CRH production is associated with preterm delivery (6, 7, 8). Thus, the mechanisms governing CRH synthesis have become of considerable interest. A variety of endogenous factors are known to regulate placental CRH production, including norepinephrine, acetylcholine, IL-1, and vasopressin (9, 10, 11). In particular, glucocorticoids stimulate placental CRH production and gene expression, in contrast to their inhibitory effects in the hypothalamus (11, 12).

Human placental syncytiotrophoblasts also synthesize large amounts of estrogens, using dehydroepiandrostenedione sulfate (DHEA-S) from the fetal adrenal as a precursor (13, 14). In the chimpanzee and gorilla, a strong correlation between maternal plasma E2 and CRH concentration has been reported (15). Previous studies have also shown that fetal adrenal DHEA-S production can be stimulated by placental CRH (16). In the hypothalamus, estrogen stimulates CRH gene expression (17, 18), and this effect may involve modulation of CRH expression through binding sites for ER in the CRH gene 5'-flanking regulatory region (19). The presence of ER in placental and cultured human syncytiotrophoblasts (20, 21) suggests that estrogen may directly regulate CRH, not only in the hypothalamus, but also in the placenta.

To elucidate the regulation of CRH synthesis by estrogen, we observed the effects of E2 on CRH gene expression in placental cells and explored the molecular mechanism. We show that E2 inhibits, whereas the estrogen antagonist ICI 182780 (ICI) induces, placental CRH production at protein and mRNA levels. These inhibitory E2 effects result from down-regulation of CRH gene transcription through an ER{alpha} mediated mechanism.

Materials and Methods

Reagents

17ß-Estradiol (E2), 4-hydroxytamoxifen (OTH), and diethylstilbestrol (DES) were obtained from Sigma-Aldrich (Sydney, Australia). ICI was purchased from Tocris Cookson (Bristol, UK).

Cell culture

Human term placentas were obtained from normal pregnant women after spontaneous vaginal delivery or elective cesarean section. Collections of placentas were performed with the approval of both the Hunter Area Health Service and the University of Newcastle human ethics committees. Cytotrophoblasts were obtained and cultured as described previously (22).

JEG-3 cells were obtained from the Kolling Medical Research Institute, University of Sydney. Cells were maintained and subcultured in phenol red-free DMEM (Life Technologies, Inc., Rockville, MD) containing 10% fetal calf serum (TRACE, Melbourne, Australia).

Quantitative RT-PCR

On d 3 after plating, primary placental cells were fed with fresh phenol red-free DMEM without fetal calf serum with or without steroids. Steroid solutions were diluted from stock (in absolute ethanol) to achieve a final concentration of ethanol of 0.01% and a final concentration of steroid as indicated. Cells fed without hormone received the same volumes of ethanol vehicle. Each treatment was performed in triplicate wells. Cells were harvested 24 h after treatment.

Total RNA was isolated by RNeasy Mini Kit (QIAGEN, Clifton Hill, Australia). First strand cDNA was synthesized from 1 µg RNA using Superscript II first strand synthesis kit (Life Technologies, Inc.). Quantitative PCR amplifications were performed with SYBRGreen (Applied Biosystems, Scoresby, Australia) using an ABI Prism 7700 Sequence Detector system in 25 µl reaction for 40 cycles (15 sec at 95 C and 1 min at 60 C). Primers were designed from human ERs and human CRH sequences in GenBank to span introns. Estrogen receptor (ER){alpha} cDNA was amplified using primers 5'-CGGCATTCTACAGGCCAAATT-3' and 5'-ATCATCTCTCTGGCGCTTGTG-3' (expected size, 379 bp). The primers 5'-TCCCTGGTGTGAAGCAAGATC-3' and 5'-CGCCGGTTTTTATCGATTGT-3' were used to amplified a product of 278 bp for ERß. To amplify CRH cDNA, primers 5'-AAGAAAAAGAGAGTGGGAACAGTAAAGA-3' and 5'-CACTCGCTTCCCAGGCG-3' were used to obtain a product of the expected size of 124 bp. Primers used to amplify the human 18S cDNA were 5'-CCCGGGGCCGGCTGGTGTGGCACCAGACTTGC-3' and 5'-GGCCGCGGCCACGGGTGACGGGGAATCAG-3'. The relative amount of target was calculated using the 2-{Delta}{Delta}CT method (CT: refers to the threshold cycle for target amplification) (Applied Biosystems, ABI PRISM 7700 Sequence Detection System User Bulletin 5). The relative efficiencies of target and reference gene amplification were tested according to the manufacturer (Applied Biosystems, ABI PRISM 7700 Sequence Detection System User Bulletin 2) and shown to be similar.

CRH RIA

CRH immunoreactivity in the culture medium was assayed by RIA performed as previously described (23). The concentrations of CRH immunoreactivity in media were expressed as pg/106 cells and normalized to vehicle.

Transient transfection

Luciferase reporter plasmids (Promega Corp., Madison, WI) were used for transient transfections. The 5.5-kb CRH 5'-flanking DNA was isolated from human CRH genomic clone, CRH 1001+ (a gift from Dr. J. Majzoub, Harvard University, Boston, MA), and linked to the luciferase reporter gene (24, 25). The expression vector for ER{alpha} (pCMV-ER{alpha}) was a gift from Dr. B. S. Katzenellenbogen (University of Illinois, Urbana, IL). Transient transfections used a calcium-phosphate method (26). One day before transfection, JEG-3 cells were plated in six-well plates at 5 x 105 cells/well. On the day of transfection, cells were transfected with 0.8 ml of HEPES buffered saline-CaCl2 solution containing 30 µg DNA and 4 µg control DNA (prolactin-thymidine kinase vector, Promega Corp.) and incubated in 5% CO2 at 37 C. Eight hours later, culture media were changed to DMEM with 10% charcoal-stripped serum and treated with E2, ICI, DES, or ethanol vehicle. Luciferase assay was carried out 24 h later with the dual luciferase assay kit (Promega Corp.). Data shown are normalized to basal activity.

Statistical analyses

Statistical analyses were carried out using Student’s paired t tests. The values are expressed as the mean ±SEM. Multiple comparisons were statistically compared by two-way ANOVA.

Results

Effects of E2 and ER agonist/antagonist on CRH mRNA and protein levels in placental cells

E2 inhibits CRH mRNA as well as protein in primary placental cells. Upon treatment with 10-7 M E2 CRH mRNA decreased to 74% of the basal level (P < 0.01) as determined by quantitative RT-PCR (Fig. 1AGo), which is paralleled by a decrease in CRH protein content in culture media as determined by RIA (Fig. 1BGo). This inhibitory effect of E2 was dose dependent, as was seen when the cells were exposed to E2 at 10-7–10-5M (Fig. 1Go). Using quantitative RT-PCR, we show that ER{alpha} is the predominant ER in primary cultured cells and tissue, although ERß is detectable at very low levels (Fig. 2Go).



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  		Figure 1. Effects of E2 on CRH mRNA and protein levels in primary placental cells. Cells were treated with 10-7–10-5 M E2 for 24 h, then total RNA was extracted and culture supernatants were collected. A, CRH mRNA was measured by quantitative PCR and normalized to 18S mRNA. B, CRH protein in culture supernatant of primary placental cells was determined by RIA. Results represent the mean ± SEM from five independent experiments. **, Difference from the vehicle value (P < 0.01).

 


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  		Figure 2. Identification of ER{alpha} and ERß in primary placental cells and tissue. ER{alpha} and ERß mRNA levels in primary placental cells and tissue were measured by real-time quantitative PCR. The amounts of ER mRNA were normalized to 18S mRNA.

 
A nonsteroidal ER agonist, DES, exerted similar effects to E2. A complete ER antagonist, ICI, blocked repression of CRH gene expression by E2 when it was added together with E2. ICI alone up-regulated CRH mRNA expression by 2.8-fold (P < 0.01) (Fig. 3AGo), and also increased CRH protein levels in the media by 130% (Fig. 3BGo). An ER{alpha} mixed agonist/antagonist and ERß antagonist, OTH, did not antagonize the effect of E2 and exhibited agonist activity, similar to that of E2 (Fig. 3Go).



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  		Figure 3. ER agonist and antagonist activity in placental cells. Primary placental cells were treated with 10-6 M DES, 10-6 M ICI, and 10-6 M OTH with or without 10-6 M E2 for 24 h, then total RNA was extracted and culture media were collected for measuring CRH mRNA and protein levels. A, CRH mRNA levels in cells; B, CRH protein level in culture media. Results represent the mean ± SEM from five independent experiments. **, P < 0.01 as indicated vs. corresponding vehicle controls.

 
E2 represses and ICI 182780 stimulates CRH promoter activity

To determine if the opposite effects observed for E2 and ICI on CRH levels act through the promoter region of the CRH gene, JEG-3 cells were cotransfected with CRH luciferase-reporter fusion plasmids and an ER{alpha} expression plasmid. Significant E2 mediated repression of CRH promoter activity and ICI mediated up-regulation of CRH promoter activity (P < 0.01) was observed with the reporter plasmids containing 5500 bp or 4300 bp of the CRH promoter region (Fig. 4Go).



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  		Figure 4. E2 inhibits and ICI stimulates CRH promoter activity. JEG-3 cells were transfected with 30 µg of the indicated CRH reporter plasmid DNA and 2.5 µg ER{alpha} plasmid DNA. Cells were treated with E2 and ICI (10-6 M) for 24 h. Results represent the mean ± SEM from three independent experiments. **, P < 0.01 as indicated vs. corresponding vehicle controls.

 
Discussion

Placental CRH has been implicated in the control of the length of human pregnancy (6, 7, 8). Specifically, the rate of rise of maternal plasma CRH is related to the duration of gestation (6). More recently, Giussani et al. (27) suggested that maternal treatment with E2 stimulates placental CRH production in vivo in the rhesus monkey. No ER is detectable in the placenta of the rhesus monkey (28), and therefore these results suggested that an indirect pathway is involved in estrogen regulation of placental CRH synthesis in this species. However, how estrogen controls CRH gene expression in human placental cells is not well documented.

Using primary placental cells, we found that E2 has an inhibitory affect on CRH gene expression in a dose-dependent manner. Significant inhibition is seen at 10-7 M, which is within the range of the plasma-free E2 in women in the third-trimester pregnancy (29). A nonsteroidal estrogen agonist DES exhibited similar effects on CRH gene expression, indicating that estrogen repression of the CRH gene is through actions at the ER rather than an effect of E2 metabolites. This result is supported by the transfection analysis that showed that E2 inhibits CRH gene promoter activity. Therefore, we conclude that estrogen inhibits CRH gene expression in human placental trophoblasts.

Our results show that the E2 effects are mimicked by OTH, an ER{alpha} agonist/ antagonist and an ERß antagonist, but are antagonized by the pure ER antagonist ICI. Transfection studies in JEG-3 cells also show that E2 inhibition of the CRH promoter is enhanced when ER{alpha} is cotransfected, consistent with ER{alpha} involvement in the regulation of CRH synthesis by E2. It has recently been demonstrated that ER{alpha} and ERß may form heterodimers to regulate the transcription of a reporter gene (30, 31). We have found that placental cells express predominantly the ER{alpha} form of the receptor. The repression of CRH expression in the presence of OTH indicates that ER{alpha} is involved in the regulation of CRH by E2, but as ERß is expressed at very low levels we cannot exclude the possibility that the two subtypes of ER form a heterodimer complex to achieve the observed repression of CRH mRNA levels.

We show that E2 represses and ICI activates CRH gene transcription in placental cells. This regulatory pattern of gene transcription by ER agonist and antagonist is consistent with other reports on estrogen action (32, 33). However, our results are not in agreement with the report of Dibbs and colleagues (34) that ER has no effect on CRH gene transcription in transfected CV-1 cells. Our experiments were conducted in a choriocarcinoma cell line that has been widely used as a model of placental trophoblasts for studies of gene expression, including the CRH gene (35, 36, 37). Our results are consistent with a report of CRH negative regulation by E2 in human endometrial cells (38). As estrogen regulation of gene expression is not only dependent on the gene itself but also cell context, it is important to note that we also demonstrate that E2 inhibits and ICI stimulates CRH gene expression in primary placental cells.

Placental syncytiotrophoblasts not only synthesize CRH and estrogens but also express the ER. The rise in CRH mRNA and protein in the presence of the pure ER antagonist suggests that estrogen has a tonic inhibitory effect on placental CRH gene expression in vivo. There are various endogenous factors associated with pregnancy that are known to stimulate CRH production, such as glucocorticoids, prostaglandin E2, catecholamines, and IL-1 (9, 10, 11). The positive feedback loop between glucocorticoid and placental CRH is well documented and thought to contribute to human parturition (11, 12). In addition to these stimulatory factors, a few factors that inhibit CRH secretion and production, such as nitric oxide and progesterone, have also been reported (22, 39), although nitric oxide only inhibits CRH secretion not synthesis (22). A tonic inhibitory effect of estrogen on CRH gene expression might therefore be important in restraining CRH production. The balance between the up-regulation of CRH production by stimulatory factors and down-regulation of CRH synthesis by inhibitory factors, such as estrogen, may be crucial for the determination of gestational length.

In conclusion, we have demonstrated that, in primary placental cells, E2 inhibits CRH synthesis through ER{alpha}mediated mechanisms. This effect may have important physiological consequences in human pregnancy.

Acknowledgments

We thank the nursing and medical staff of the delivery suite, John Hunter Hospital, for their cooperation in obtaining placenta; J. A. Majzoub and B. S. Katzenellenbogen for providing plasmids; M. Bowman for the preparation of CRH tracer; and X. L. Tang for assistance in preliminary studies.

Footnotes

This work was supported by the Natural Science Foundation of China No. 39870300 (to X.N.) and the National Health and Medical Research Council of Australia (to R.S.).

Abbreviations: DES, Diethylstilbestrol; DHEA-S, dehydroepiandrostenedione sulfate; E2, 17ß-estradiol; ER, estrogen receptor; ICI, estrogen antagonist ICI 182780.

Received January 24, 2002.

Accepted May 2, 2002.

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