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Biology of Reproduction 61, 85-90 (1999)
©Copyright 1999 Society for the Study of Reproduction, Inc.

Articles

Regulation of Monocyte Chemotactic Protein-1 Expression in Human Endometrial Stromal Cells by Estrogen and Progesterone1

Aydin Arici2,a, Levent M. Senturka, Emre Selia, Mert O. Bahtiyara, and Grace Kima

a Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520-8063


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
There is a cyclicity in the number of endometrial macrophages that is most likely secondary to changes in steroid hormone levels. One cytokine that controls macrophage migration is monocyte chemotactic protein-1 (MCP-1). In the endometrium, highest levels of MCP-1 are detected perimenstrually, when estrogen levels are low; however, when estrogen levels are high (around the time of ovulation), MCP-1 levels are lowest. We hypothesized that sex steroids may be involved in the regulation of macrophage migration by regulating MCP-1 expression. We investigated the regulation of MCP-1 expression in human endometrial stromal cells by estradiol 17ß (E2) and progestins. We found that MCP-1 mRNA levels decreased in response to E2 (5 x 10-8 M), with biphasic nadirs at 8 h and 24 h. MCP-1 protein production was also inhibited by E2 in a concentration-dependent manner. Tamoxifen, an anti-estrogen, alone (10-7 M) did not affect MCP-1 expression, but it reversed the E2-induced inhibition up to 80%. Progesterone (10-7 M) alone slightly decreased MCP-1 levels, and the combination of E2 and progesterone further decreased them, but that decrease was not different from that observed using E2 treatment alone. In summary, we found that E2 inhibits MCP-1 expression in endometrial stromal cells, and we speculate that E2 may control endometrial macrophage migration by regulating MCP-1 expression.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The human endometrium undergoes proliferation, differentiation, and shedding in response to changes in sex steroid hormone levels throughout the menstrual cycle. Coincident with these fluctuations is the change in the number and type of leukocytes present in the endometrium. Around the time of implantation, at the mid-secretory phase of the cycle, macrophages and large granular lymphocytes aggregate in the endometrial stroma [1]. Premenstrually, neutrophils and macrophages migrate to the endometrium [2]. The cyclicity of leukocyte populations in the endometrium suggests a regulation by sex steroids. Recent evidence, however, demonstrate that while leukocytes may express estrogen receptors [3], they do not manifest progesterone receptors [4]. Thus, the effects of sex steroids on the leukocyte population in the endometrium may involve some indirect mechanisms. Indeed, the endometrium is a known source for multiple cytokines that could act to regulate the migration, replication, and/or function of these leukocytes.

A number of chemokines are expressed in the cycling endometrium, such as interleukin-8 [5], which chemoattracts neutrophils, and RANTES (regulated upon activation, normal T cell expressed and secreted) [6], which chemoattracts monocytes and T cells. Another potent chemoattractant for monocytes is monocyte chemotactic protein-1 (MCP-1), a 76-amino-acid basic protein of the ß-chemokine family [7]. It is encoded by a single copy gene, located on chromosome 17, that has a promoter region containing binding sites for AP-1 and for NF{kappa}B [8]. In addition to attracting monocytes, MCP-1 to a lesser degree attracts and activates T lymphocytes [9], basophils [10], and natural killer cells [11]. MCP-1 is produced by a variety of cells, including monocytes and lymphocytes [12], fibroblasts [13], endothelial cells [14], and smooth muscle cells [15].

We have previously shown that MCP-1 is produced by endometrial stromal and glandular cells in culture [16]. In the human endometrium, highest levels of MCP-1 mRNA are detected perimenstrually, when estrogen levels are low. When estrogen levels are high (around the time of ovulation), MCP-1 levels are lowest [16, 17]. Immunohistochemistry reveals a higher level of MCP-1 expression in glands than in stroma [18]. MCP-1 expression in gland cells is weakly regulated. This is in contrast to the low constitutive but highly regulated MCP-1 expression observed in stromal cells [16]. Factors that up-regulate MCP-1 in stromal cells include cytokines such as interleukin-1, tumor necrosis factor-{alpha}, interferon-{alpha}, and platelet-derived growth factor [16]. It is interesting to note that, in contrast to the high levels of MCP-1 observed in endometrial gland cells, MCP-1 is not expressed in the Ishikawa cells, a cell line derived from a well-differentiated endometrial adenocarcinoma (unpublished results).

We thus hypothesized that sex steroids may be involved in the regulation of macrophage migration in the endometrium by way of regulation of MCP-1 expression. In this study, we investigated the regulation of MCP-1 mRNA and protein production by estrogen and progesterone in human endometrial stromal cell culture. We focused our studies on stromal cells since MCP-1 is relatively unregulated in gland cells.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tissue Collection and Cell Culture

Endometrial tissue samples were obtained from women undergoing hysterectomy for benign disease. Informed consent was obtained from each woman before surgery using protocols approved by the Human Investigation Committee of Yale University. Tissue samples were placed in Hanks' balanced salt solution (HBSS) and transported to the laboratory for cell culture. Endometrial cells were dispersed by incubation of tissue minces in HBSS that contained HEPES (25 mM), penicillin (200 U/ml), streptomycin (200 mg/ml), collagenase (2 mg/ml, 15 U/mg), and deoxyribonuclease (0.2 mg/ml, 1500 U/mg) for approximately 20 min at 37°C with agitation. The dispersed endometrial stromal cells were separated from glands by filtration through a wire sieve (73-µm-diameter pore). Endometrial glands remained largely undispersed and were retained by the sieve, while stroma passed through into the filtrate.

Stromal cells were plated in Ham's F-12: Dulbecco's modified Eagle's medium (1:1, v:v) containing antibiotics and antimycotics (1%, v:v) and fetal bovine serum (10%, v:v). Cells were plated in plastic flasks (75 cm2), maintained at 37°C in a humidified atmosphere (5% CO2 in air), and allowed to replicate to confluence. Thereafter, cells were passaged by standard methods of trypsinization and were plated in either 100-mm-diameter Petri dishes for RNA extraction or in 24-well plates for collection of supernatants. Endometrial stromal cells after first passage were characterized as described previously [19] and were found to contain 0–7% epithelial cells, no endothelial cells, and 0.2% macrophages. In each experiment, cells were treated with serum-free, phenol red-free medium for 24 h before treatment with steroid hormones was initiated. Each experimental set-up was repeated on at least three occasions using endometrial stromal cells obtained from three different patients. Cell viability was assessed by exclusion of trypan blue dye (0.04% in PBS; w:v). Approximately 98% of cells in culture excluded the trypan blue dye after treatment with test agents.

Northern Analysis

Total RNA was extracted using Trizol (Gibco BRL, Grande Island, NY) and size-fractionated by electrophoresis in 1% formaldehyde-agarose gels, transferred electrophoretically to Hybond-N+ membranes (Amersham, Arlington Heights, IL), and cross-linked to the membranes using ultraviolet light. Prehybridization was conducted for at least 4 h at 65°C in buffer containing NaCl (0.9 M), Tris-Cl (90 mM, pH 8.3), EDTA (6 mM), 5-strength Denhardt's solution, SDS (0.1%, w:v), sodium pyrophosphate (0.1%, w:v), and salmon sperm DNA (0.2 mg/ml). Hybridizations were conducted for 16 h at 65°C in the same buffer with the addition of a 30-mer oligonucleotide DNA probe complementary to a specific sequence of MCP-1 mRNA and radiolabeled with [{gamma}-32P]ATP [20]. Membranes were washed twice with double-strength SSC (single-strength SSC is 0.15 M sodium chloride, 0.015 M sodium citrate) and SDS (0.1%, w:v) for 15 min at room temperature and once for 30 min at 65°C. Autoradiography of the membranes was performed at -80°C using Kodak X-Omat AR film (Eastman Kodak, Rochester, NY).

The autoradiographic bands were quantified by using a laser densitometer (Molecular Dynamics, Sunnyvale, CA). The presence of similar amounts of total RNA in each lane was verified by visualization of ethidium bromide-stained 28S and 18S ribosomal RNA subunits. The MCP-1 mRNA band was also normalized in some experiments using the value for the corresponding glyceraldehyde-3-phosphate dehydrogenase (G3PDH) mRNA level, thus correcting for any variation in the amount of mRNA applied to each lane.

MCP-1 ELISA

MCP-1 in culture media of endometrial stromal cells was quantified using an ELISA from R&D Systems (Minneapolis, MN). According to the manufacturer, there is no measurable cross-reactivity with other known cytokines in this assay. The sensitivity for MCP-1 was 4.7 pg/ml in media. The intra- and interassay coefficients of variation were 4.9% and 5.9%, respectively.

Statistical Analysis

Statistical calculations were performed using Sigmastat for Windows, version 2.0 (SPSS, Chicago, IL). Because the levels of MCP-1 in culture media were normally distributed, they were analyzed with ANOVA. For pair-wise multiple comparisons a post-hoc Tukey test was used.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Regulation of MCP-1 mRNA Expression and Protein Production in Endometrial Stromal Cells by Estradiol

Endometrial stromal cells maintained in serum-free medium expressed MCP-1 mRNA (0.7 kilobases [kb]). The MCP-1 mRNA level decreased markedly in response to estradiol-17ß (E2; 5 x 10-8 M). This decrease was evident as early as 2 h and became more pronounced by 6 h (Fig. 1, left panel). We also assessed the effect of longer treatments of E2 on MCP-1 mRNA expression. Cells were treated for 4–24 h with E2 (5 x 10-8 M) or vehicle. In the control group (vehicle only), a simple medium change decreased MCP-1 mRNA levels, which returned to baseline at 12 h. Compared to control, E2 induced inhibition of MCP-1 expression at two time points: 8 h and 24 h. Experiments on the time course of the estrogen effect on MCP-1 mRNA levels were repeated on three occasions using endometrial stromal cells obtained from three different patients, and similar results were observed. A representative Northern blot is presented in Figure 1 (right panel).



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  		Fig. 1. Time course of E2-mediated inhibition of MCP-1 mRNA levels. Left panel) Endometrial stromal cells in culture were placed in serum-free medium 24 h before incubation with culture medium containing E2 (5 x 10-8 M) for 1–6 h. Right panel) Cells were placed in serum-free medium 24 h before incubation with culture medium containing E2 (5 x 10-8 M) for 4–24 h. At the end of the incubation period, the culture media were removed, and total RNA was prepared from the cells. MCP-1 mRNA was evaluated by Northern analysis of total RNA (20 µg per lane). The bar graph in the left panel represents the MCP-1 mRNA ratio at each time point to time 0. The bar graph in the right panel represents the MCP-1 mRNA ratio of the cells treated with E2 to the control cells for each time point.

We then assessed the effect of E2 on MCP-1 protein production by endometrial stromal cells in culture. MCP-1 production started to decrease in response to 8 h of treatment with E2 compared to control, but the difference was not significant. The levels of MCP-1 decreased markedly in response to 24 h of treatment with E2. The decrease in the MCP-1 production by stromal cells was dependent on the concentration of E2 (10-12 to 10-6 M) and was significant (p < 0.01) at concentrations above 10-9 M (Fig. 2).



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  		FIG. 2. Inhibition of MCP-1 production by endometrial stromal cells in culture by E2. Endometrial stromal cells were placed in serum-free medium 24 h before incubation with culture medium alone (control) or with culture medium containing various concentrations of E2 (10-12 M to 10-6 M) for 24 h. Culture media were collected, and MCP-1 was quantified by ELISA. Data are mean ± SEM for four replicates. p < 0.01 between control and concentrations above 10-9 M.

Effect of Tamoxifen on MCP-1 mRNA Expression in Endometrial Stromal Cells

We evaluated the effect of tamoxifen, an anti-estrogen, on MCP-1 expression in endometrial stromal cells in culture. Tamoxifen treatment alone (10-7 M) for 8 h did not affect MCP-1 mRNA expression. On the other hand, when used together with E2 (10-10 M to 10-8 M), tamoxifen reversed the E2-induced inhibition of MCP-1 expression up to 80% (Fig. 3).



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  		FIG. 3. Effect of tamoxifen on MCP-1 mRNA levels in endometrial stromal cells. Endometrial stromal cells in culture were placed in serum-free medium 24 h before incubation with culture medium alone (control) or with culture medium containing E2 (10-10 M to 10-8 M) or E2 with tamoxifen (10-7 M) for 8 h. At the end of the incubation period, the culture media were removed, and total RNA was prepared from the cells. MCP-1 mRNA was evaluated by Northern analysis of total RNA (20 µg per lane).

Effect of Progestins on MCP-1 mRNA and Protein Expression in Endometrial Stromal Cells

To determine the effect of progesterone on MCP-1 expression, endometrial cells were treated with progesterone (10-7 M) for 1–6 h. Progesterone induced an inhibition of MCP-1 mRNA similar to a simple medium change. The combination of E2 (5 x 10-8 M) and progesterone further inhibited the MCP-1 mRNA levels in a time-dependent manner, with the strongest effect observed at 6 h of treatment, but the inhibition was not significantly more than that observed in E2-only treated cells (Fig. 4).



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  		FIG. 4. Time course of progesterone-mediated inhibition of MCP-1 mRNA levels. Endometrial stromal cells in culture were placed in serum-free medium 24 h before incubation with culture medium containing progesterone (10-7 M) alone or together with E2 (5 x 10-8 M) for 1–6 h. At the end of the incubation period, the culture media were removed, and total RNA was prepared from the cells. MCP-1 mRNA was evaluated by Northern analysis of total RNA (20 µg per lane). P, progesterone.

We then assessed the effect of progesterone on MCP-1 protein production by endometrial stromal cells. MCP-1 protein levels were not different after 8 h of treatment with progesterone (10-9 M to 10-7 M). We observed some decrease in MCP-1 production after 24 h of progesterone treatment, but the decrease was statistically significant (p < 0.05) only at 10-7 M (Fig. 5).



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  		FIG. 5. Inhibition of MCP-1 production by endometrial stromal cells in culture by progesterone. Endometrial stromal cells were placed in serum-free medium 24 h before incubation with culture medium alone (control) or culture medium containing various concentrations of progesterone (10-9 M to 10-7 M) for 24 h. Culture media were collected, and MCP-1 was quantified by ELISA. Data are mean ± SEM for four replicates. p < 0.05 between control and 10-7 M.

The effect of the specific progesterone antagonist mifepristone (RU-486) in antagonizing the progestin-induced inhibition of MCP-1 production was also investigated. Endometrial stromal cells were treated with medroxyprogesterone acetate (MPA; 10-8 M) alone, or together with RU-486 (10-7 M) or E2 (5 x 10-8 M) for 24 h. MCP-1 protein production was then quantified using an ELISA. We observed a modest (30%) yet significant (p < 0.05) inhibition of MCP-1 production by MPA that was reversed by RU-486. E2 alone markedly decreased (65%; p < 0.01) the MCP-1 protein levels, and the addition of MPA did not change these levels significantly (Fig. 6).



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  		FIG. 6. Effect of RU-486 in antagonizing the progestin-induced inhibition of MCP-1 production. Endometrial stromal cells were placed in serum-free medium 24 h before incubation with culture medium alone (control), or culture medium containing MPA (10-8 M) alone or together with RU-486 (10-7 M) or E2 (5 x 10-8 M) for 24 h. Culture media were collected, and MCP-1 was quantified by ELISA. Data are mean ± SEM for three replicates.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Human endometrium is involved in multiple unique functions. It undergoes cyclic growth and shedding, and it is capable of blastocyst implantation, immune tolerance, regulation of trophoblast invasion, infectious agent control, and efficient disposal of blood and cellular debris with menstruation. Endometrium is hormonally responsive and consists of glandular epithelium and stroma, as well as leukocytes. The number and type of leukocytes in endometrium vary in a predictable manner, suggesting some kind of endocrine and paracrine control. Endometrium is a site of synthesis of multiple cytokines that act to regulate the migration, replication, and/or function of leukocytes. MCP-1, through its monocyte chemotactic and activating properties, seems to be one of these regulators since it has been shown to be produced by endometrial stromal and glandular cells in culture [16]. Its expression in endometrium is increased premenstrually and decreased around ovulation coincident with macrophage accumulation and depletion, respectively. In this study, we hypothesized that estrogen and progesterone may be involved in endometrial macrophage migration and examined the effects of E2 and progesterone on the regulation of MCP-1 in human endometrial stromal cells in culture.

We found that treatment of endometrial stromal cells with E2 significantly inhibited MCP-1 mRNA and protein expression. Progestins also inhibited MCP-1 protein production, although this inhibition was less than that induced by estrogen. Estrogen and progesterone together may act as a potent anti-inflammatory combination since estrogen induces the expression of progesterone receptor, making cells more responsive to progesterone's inhibitory effects. Consistent with our study is the recent finding that in the peritoneal cavity, estrogen serves as an anti-inflammatory agent by inhibiting peritoneal adhesion formation in a murine model [21]. In addition, progesterone has been implicated in the immunosuppression that occurs during pregnancy [22].

Recently, MCP-1 levels in endometrial samples throughout the menstrual cycle have been examined by immunohistochemistry. Highest levels were detected premenstrually, when levels of estrogen and progesterone decrease as the result of luteolysis. Lowest levels of MCP-1 were detected at the time of ovulation, when estrogen levels surge [17]. Moreover, these cyclic levels of MCP-1 have been shown to correspond to cyclic levels of leukocytes in the endometrium; the number of macrophages rises during the premenstrual stage and falls at ovulation [16, 17]. Changes in circulating estrogen and progesterone levels, then, may indirectly account for changes in the number and types of resident leukocytes in the endometrium. However, the elevated MCP-1 levels and increase in macrophage population in the endometrium during the mid-secretory phase cannot be accounted for fully by sex steroid levels: the high concentrations of estrogen and progesterone at this time would hypothetically inhibit levels of MCP-1 expression and therefore suppress macrophage recruitment. Such a discrepancy demonstrates the importance of in vivo considerations. Many other factors may be responsible for the control of MCP-1 levels in vivo. One such candidate is interleukin-1, which significantly stimulates MCP-1 expression in endometrial cell cultures and is elevated in the mid-secretory phase.

At present, the mechanism(s) by which sex steroid hormones act to inhibit MCP-1 expression is unknown. Sequencing of the promoter region of the MCP-1 gene, while not yet complete, has failed to reveal either a palindromic estrogen response element or a progesterone response element. Thus, rather than directly controlling the transcription of MCP-1, gonadal steroids may act through another protein or series of proteins to regulate its expression. We have performed multiple experiments to understand the time course of the regulation of MCP-1 by E2. Our findings suggest that E2 may act at two levels to inhibit MCP-1 mRNA expression. Interexperimental variability does not allow us to pinpoint a single time point exactly, but we can provide a time interval. We have consistently observed an initial rapid inhibition of MCP-1 mRNA expression around 6–8 h of estrogen treatment. While E2 may act directly on a specific silencer sequence, it may also act by stimulating the expression of transcription factors such as c-jun or c-fos, which then may act on the promoter region to suppress transcription. The second inhibition, which occurs around 18–24 h, is much later and more prolonged. The mechanism for estrogen's action in this scenario may involve stimulating the production of other growth factors or cytokines, which in turn may act to inhibit MCP-1 levels. For instance, E2 up-regulates levels of transforming growth factor ß3 (TGFß3), a potent inhibitor of MCP-1 expression [23], in endometrial cells [24]. Conversely, estrogen may inhibit the expression of a factor that normally acts to stimulate MCP-1 expression.

MCP-1 is up-regulated by oxidative stress, and antioxidants inhibit the production of MCP-1 [25]. Our results confirm that changing the medium that contains antioxidants causes a down-regulation of MCP-1. This down-regulation is believed to be secondary to a decrease in DNA binding activity of NF{kappa}B, a transcription factor necessary for MCP-1 gene expression [26]. We thus investigated the question whether the down-regulation of MCP-1 occurred through in vitro antioxidant properties of E2. Tamoxifen, another in vitro antioxidant and also an estrogen antagonist, failed to inhibit the MCP-1 expression when used alone. Moreover, when used together with E2, tamoxifen reversed the inhibition of MCP-1 by E2. This suggests that the inhibitory effect of E2 on MCP-1 is not due to its in vitro antioxidant activity but is, rather, an estrogen receptor-mediated activity.

In summary, we have found that estrogen acts to inhibit MCP-1 expression in a time- and concentration-dependent manner. While we can conclude that estrogen suppresses MCP-1 expression in human endometrial cells in vitro, the complexity of interactions with other factors in the human endometrium necessitates further studies to elucidate the in vivo actions of sex steroids.


   FOOTNOTES
 
1 This research was supported by a National Institutes of Health Grant (HD 01041) to A.A. Back

2 Correspondence: Aydin Arici, Yale University School of Medicine, Department of Obstetrics and Gynecology, 333 Cedar Street, New Haven, CT 06520–8063. FAX: 203 785 7134; aydin.arici{at}yale.edu Back

Accepted: February 15, 1999.

Received: October 30, 1998.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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