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Regular Article |
a Yale University School of Medicine, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, New Haven, Connecticut 06520-8063
ABSTRACT
Implantation involves a complex set of events, including apoptosis in endometrial cells. Apoptosis in human endometrium coincides with the implantation window, suggesting a potential role for steroid hormones in its regulation. Fas ligand (FasL) is one of the mediators of apoptosis in differentiated cells and in embryonic development. Interaction of FasL with its receptor, Fas, induces apoptosis through autocrine and paracrine signaling. We hypothesized that FasL expression in human endometrium is cycle-dependent and that sex steroid hormones regulate FasL expression. We first studied menstrual cycle-dependent expression of FasL in human endometrium by immunohistochemistry in 24 samples. We then investigated the in vitro regulation of FasL expression by ovarian steroid hormones. Throughout the menstrual cycle immunohistochemical staining intensity was stronger in the functional layer of endometrium than it was in the basal layer. FasL immunoreactivity increased gradually through the mid- and late-proliferative phases in both endometrial stromal and glandular cells. Strong FasL expression was observed throughout the late-proliferative and secretory phases. Semiquantitative reverse transcription-polymerase chain reaction analysis in cultured endometrial glandular cells demonstrated that estradiol and progesterone stimulate FasL mRNA expression. Western blot analysis in endometrial glandular and stromal cells in culture revealed that estradiol alone and in combination with progesterone up-regulated FasL protein expression. These results suggest that estradiol and progesterone may have a role in the regulation of maternal immunotolerance for the implantation of a semiallograft embryo by inducing FasL expression. We speculate that increased FasL expression may mediate the apoptosis of endometrial cells and thus may play a role in trophoblast invasion.
apoptosis, estradiol, implantation, progesterone, uterus
INTRODUCTION
Apoptosis, the process of physiologic, programmed cell death, is regulated by various proteins including Bax, Bcl-2, and Fas. Fas (CD95) is a 45-kDa type I membrane protein that belongs to the tumor necrosis factor/nerve growth factor receptor family [1]. The Fas ligand (FasL) is a 37-kDa protein that belongs to the tumor necrosis factor superfamily. The Fas-FasL interaction is one of the essential events in the induction of apoptosis [2, 3].
Implantation of the blastocyst into the receptive endometrium is the initial step in the set of events that includes cell differentiation, apoptosis, invasion, and extracellular matrix remodeling, all of which are necessary for a successful pregnancy. Apoptosis has a role in both implantation and decidualization [4, 5]. During human implantation, attachment of the embryo to the luminal epithelium is followed by decidualization of endometrial stromal cells. Displacement of the luminal epithelium is associated with the death of the epithelial cells by apoptosis, which can be blocked by actinomycin-D, a transcription inhibitor, indicating programmed cell death that requires new mRNA synthesis [6].
Important changes occur in the immune milieu of the human endometrium during decidual differentiation. Large granular lymphocytes, T lymphocytes, and macrophages comprise 70%, 20%, and 10% of the leukocyte population, respectively, in the decidua [7]. These cells, when in direct contact with invading trophoblasts, are believed to play a role in immune tolerance at the maternal-placental interface. Fas/FasL signaling in activated T lymphocytes induces an immune-privileged environment in Sertoli cells [8] and the cornea [9], and the Fas-FasL interaction was recently suggested as the mechanism for the immune tolerance at the decidua-trophoblast interface [10, 11].
Molecular mechanisms regulating cell death during decidualization and blastocyst implantation are still not fully understood. Decidual cell death seems be an intrinsic response regulated by the maternal hormonal milieu because the decidua goes through involution in the artificially induced deciduoma, where the embryo is absent, or when trophoblast cells are removed [12]. The regulatory effect of the decidua on trophoblast invasion is better recognized in abnormal pregnancies. The formation of placenta accreta or percreta when the decidua is absent (i.e., in the presence of uterine scars) and the ectopic pregnancy implantation are associated with a significantly increased trophoblast invasion. Recent studies on this subject, however, have revealed the potential role of the embryo in epithelial cell apoptosis during trophoblast invasion in rodents [13] and in humans [14].
We hypothesized that FasL expression in human endometrium is cycle-dependent, and that sex steroid hormones regulate FasL expression. To test our hypothesis we investigated the expression of FasL in human endometrium throughout the menstrual cycle, and we studied the in vitro regulation of FasL expression by estrogen and progesterone in endometrial stromal and glandular cells in culture.
MATERIALS AND METHODS
Tissue Collection
Endometrial tissue was obtained from human uteri after hysterectomy conducted for benign diseases other than endometrial disease or from endometrial biopsies. Informed consent in writing was obtained from each patient before surgery; consent forms and protocols were approved by the Human Investigation Committee of Yale University. The mean age of patients was 42.4 (range 34–50) yr. The day of the menstrual cycle was established from the patient's menstrual history and was verified by histological examination of the endometrium. Samples were grouped according to menstrual cycle phases: early proliferative (Days 1–5), mid-proliferative (Days 6–10), late proliferative (Days 11–14), early secretory (Days 15–18), midsecretory (Days 19–23), and late secretory (Days 24–28). Some of the endometria were embedded in OCT compound (Sakura, Torrance, CA) for immunohistochemistry and frozen at -86°C. The remaining tissues were placed in Hanks balanced salt solution (HBSS) and transported to the laboratory for separation and culture of endometrial stromal and glandular cells.
Isolation and Culture of Human Endometrial Stromal and Glandular Cells
Endometrial stromal and glandular cells were separated and maintained in a monolayer culture as described previously [15]. Briefly, endometrial tissue was digested by incubation of tissue minces in HBSS (Sigma Chemical Co., St. Louis, MO) that contained Hepes (25 mmol), penicillin (200 U/ml), streptomycin (200 mg/ml), collagenase (1 mg/ml, 15 U/mg), and deoxyribonuclease (0.1 mg/ml, 1500 U/mg) for 30 min at 37°C with agitation. The dispersed endometrial cells were separated by filtration through a wire sieve (73-µm diameter pore, Sigma). The endometrial glands (largely undispersed) were retained by the sieve, whereas the dispersed stromal cells passed through the sieve into the filtrate.
The stromal cells were plated in Ham F12/Dulbecco minimal essential medium (DMEM; 1:1 vol/vol; Sigma) and fetal bovine serum (FBS; 10% vol/vol; Gibco BRL, Rockville, MD). 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, the stromal cells were passed by standard methods of trypsinization and plated in culture dishes (100-mm diameter; Falcon, Franklin Lakes, NJ) and were allowed to replicate to confluence, which takes approximately 7–10 days. Endometrial stromal cells after first passage were characterized as described previously [15] and were found to contain 0–7% epithelial cells, no endothelial cells, and 0.2% macrophages. Experiments were commenced 1–3 days after confluence was attained. The confluent cells were treated with serum-free phenol red-free media for 24 h before treatment was initiated with test agents.
Endometrial glandular cells (largely intact glands and sheets of surface epithelium) were collected by backwashing the sieve, plated in 6-well plates, previously coated with growth factor-reduced Matrigel. Cells were maintained in DMEM containing FBS (10%), antibiotics-antimycotics (1%), and D-valine (substituted for L-valine to inhibit stromal cell growth [16]). Both glandular and stromal cells reach confluence in 7–10 days. Experiments with glandular cells were conducted 1–3 days after confluence was attained. The cells were treated with serum-free phenol red-free media for 24 h before treatment was initiated with test agents.
Cells were treated with various concentrations of 17ß-estradiol (10-11 to 10-7 M) alone or in combination with different concentrations of progesterone (10-9 M estradiol with 10-11 to 10-7 M progesterone) for 24 h for Western blot analysis and immunocytochemistry, and 3 h for reverse transcriptase-polymerase chain reaction (RT-PCR) experiments.
FasL RT-PCR
Total RNA was extracted using Trizol Reagent (Gibco BRL) according to the manufacturer's instructions. Two micrograms of sample was reverse transcribed in 20 µl of reaction mixture containing 10 mM each of dATP, dCTP, dGTP, and dTTP; 20 pmol oligo(dT); 40 U/µl ribonuclease inhibitor, 10 U/µl avian myeloblastosis virus-reverse transcriptase, and buffer (42°C for 60 min and 95°C for 5 min; model 9600 thermocycler, Perkin-Elmer, Norwalk, CT). The RT reaction was followed by a PCR conducted in a total volume of 50 µl containing 10x PCR buffer, 10 µM each of 5' and 3' primers (30 cycles at 95°C for 1 min, 60°C for 1 min, and 72°C for 1.5 min). All the components for RT-PCR were purchased from Promega (Madison, WI) with the exception of the primers, which were synthesized at Yale University, Department of Pathology. The primers used for amplification of FasL, Fas, and G3PDH have been recently described [17–19], and have the following sequences:
PCR products and molecular weight markers were separated on agarose gels containing ethidium bromide (10 mg/ml) and visualized by UV light. The intensity of each band was normalized to its corresponding G3PDH band to semiquantitatively compare values between samples.
FasL Western Blot Analysis
Total protein from the cells was extracted in a lysis buffer (50 mM Hepes pH 7.4, 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl2-6H2O, 1 mM EGTA, 100 mM NaF, 10 mM sodium pyrophosphate and protease inhibitors, 1 mM Na3VO4, 10 µg/ml leupeptin, 10 µg/ml aprotinin, and 4 mM PMSF). The protein concentration was determined by a detergent-compatible protein assay (Bio-Rad Laboratories, Hercules, CA). Samples (10 µg) were loaded and electrophoretically separated by SDS-polyacrylamide gel using 7.5% Tris-HCL Ready Gels (Bio-Rad) and electroblotted onto a Hybond electrochemiluminescent nitrocellulose membrane (Amersham Pharmacia Biotech, Buckinghamshire, UK). Equal loading of proteins in each lane was confirmed by staining the membrane with Ponceau 2S (Sigma). The membrane was blocked with 5% nonfat dry milk in PBS-T buffer (0.05% Tween-20 in PBS pH 7.4) for 1 h to reduce the nonspecific binding. The membrane was incubated for 1 h with mouse anti-human FasL monoclonal antibody (Transduction Laboratories, Lexington, KY) diluted at 1:1000, and thereafter washed with PBS-T buffer once for 15 min and twice for 5 min. The membrane was incubated for an additional 1 h with peroxidase-labeled anti-mouse immunoglobulin G (IgG; Vector Laboratories, Burlingame, CA) diluted at 1:10 000 and subsequently washed with PBS-T once for 15 min and twice for 5 min. The immunoblot was developed using a TMB peroxidase substrate kit (Vector Laboratories).
Immunohistochemistry and Cytochemistry
Endometrial tissue samples were cut at a thickness of 7 µm and fixed in cold methanol (-20°C for 20 min) and dried for 20 min at room temperature. Endometrial stromal cells were grown to preconfluence on four-chamber slides. Following treatments, chamber slides were fixed for 10 min in cold methanol (-20°C) and dried for 20 min at room temperature. After several washings in distilled water and then three times in PBS (pH 7.4) for 10 min, endogenous peroxide activity was quenched with 3% H2O2 (0.6 ml H2O2 and 5.4 ml methanol) for 10 min (both frozen sections and tissue culture slides), and rinsed in PBS-T. Sections were then incubated with the mouse anti-human FasL monoclonal antibody (Transduction Laboratories, diluted at 1:100) for 30 min at room temperature. In the negative control slides, normal mouse IgG was used instead of a primary antibody. After several rinses in PBS-T, biotinylated secondary antibody (goat anti-multispecimens immunoglobulin; Biogenex, San Ramon, CA) was applied for 30 min. Following several PBS-T rinses, culture slides were incubated with streptavidin-peroxidase complex for 30 min (Biogenex). Subsequently, slides were rinsed several times in PBS-T and then were incubated with 3-amino-9-ethyl-carbazole (AEC; Biogenex) for 10 min. Slides were lightly counterstained with hematoxylin prior to permanent mounting. For each experiment, all slides were stained in a single batch and thus received equal staining. Immunohistochemical and cytochemical staining intensity was ranked between 0 (absent) to 3 (most intense). For each tissue, an HSCORE value was derived by summing the percentages of cells that stained at each intensity and multiplying that by the weighted intensity of the staining. For example:
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Statistical Analysis
Because the levels of FasL immunohistochemistry scores in the endometrium were not normally distributed, they were analyzed with nonparametric ANOVA by ranks (Kruskal-Wallis test). Statistical calculations were performed using the Statistical Package for the Social Sciences (Chicago, IL) version 6.0 for Windows.
RESULTS
In Vivo Expression of FasL in Human Endometrium by Immunohistochemistry
Twenty-four endometrial samples were evaluated by immunohistochemistry. The distribution according to menstrual cycle phase was as follows: early proliferative (n = 5), mid-proliferative (n = 4), late proliferative (n = 4), early secretory (n = 4), mid-secretory (n = 4), and late secretory (n = 3). The early proliferative phase was characterized by a thin, relatively homogenous endometrium with simple and straight glands. By the late proliferative phase, increased thickness, tortuose glands, and separation of stromal cells by edema in the superficial layer were observed. The secretory phase was characterized by rounded nuclei and subnuclear vacuoles representing an accumulation of glycogen-rich secretions in the epithelial glands (the early secretory phase), edema in the spongiosa layer and a saw-toothed appearance of glands (the mid-secretory phase), resolution of intracellular edema and widely dilated glands filled with secretion (the late secretory phase). In all samples evaluated, both stromal and glandular cells showed immunohistochemical staining for FasL throughout the cycle, although glandular cells exhibited stronger staining than the stromal cells. FasL immunoreactivity was, interestingly, intracellularly localized in glandular cells during the early proliferative phase (Fig. 1A), whereas its expression was observed only in the apical membrane of the glandular cells during the late proliferative and throughout the secretory phases (Fig. 1B). Overall in the endometrium, FasL immunoreactivity was observed weakly in the early proliferative phase and its intensity increased gradually toward the late proliferative and early secretory phases (Fig. 1, A and B). FasL immunoreactivity was less spatially intense in the basal layer of endometrium compared with the functional layer (Fig. 1C). Mean staining intensities in stromal (Fig. 2A) and glandular (Fig. 2B) cells were compared according to menstrual cycle phases. Staining intensity for stromal cells was significantly higher in the mid-secretory phase compared with the early proliferative phase (P < 0.05, Fig. 2A), whereas glandular cells showed significantly higher staining in both mid- and late-secretory phases compared with the early proliferative phase (P < 0.05, Fig. 2B).
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Regulation of FasL Expression in Endometrial Glandular and Stromal Cells in Culture
Endometrial stromal and glandular cells plated onto tissue chamber slides were incubated with estradiol (10-9 M), progesterone (10-9 M), and estradiol in combination with progesterone (10-9 M and 10-8 M) for 24 h and cells were analyzed by immunocytochemistry. FasL immunoreactivity was observed as membranous and cytoplasmic (Fig. 1, a–d). In untreated endometrial stromal cells FasL immunoreactivity was weak (Fig. 1a). Estradiol and progesterone alone and in combination induced an increase in both intensity and distribution of FasL immunoreactivity (Fig. 1, b–d). FasL expression was also observed in untreated endometrial glandular cells (Fig. 1e). In glandular cells, similar to stromal cells, the intensity and distribution of FasL immunoreactivity increased with estradiol and progesterone alone and in combination (Fig. 1, f–h).
Fas and FasL mRNA Expression in Endometrial Cells in Culture
To evaluate whether the up-regulatory effect of estradiol and progesterone on FasL protein expression was due to increased mRNA levels, RT-PCR analysis was used. We also investigated FasL receptor (Fas) mRNA expression in human endometrium and observed that both endometrial stromal and glandular cells expressed Fas mRNA (Fig. 3a). Endometrial glandular cells were incubated with various concentrations of estradiol alone or in combination with progesterone. Untreated endometrial glandular cells were found to express FasL mRNA (Fig. 3, b and c). Estradiol alone and in combination with progesterone up-regulated FasL mRNA expression in a concentration-dependent manner compared with controls (Fig. 3, b and c).
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Regulation of FasL Protein Expression in Endometrial Cells in Culture
To investigate the regulation of FasL protein expression by ovarian steroid hormones, endometrial glandular cells were incubated with estradiol (10-11 to 10-9 M) and progesterone (10-11 to 10-7 M) alone or in combination for 24 h, and FasL protein levels were analyzed by Western blot analysis. Untreated endometrial glandular cells expressed FasL protein (Fig. 4, a–c). Estradiol stimulated the FasL expression in a concentration-dependent manner (Fig. 4a). Although progesterone also had a stimulating effect on FasL protein expression this effect was less than that observed with estradiol (Fig. 4b). However, when combined with estradiol, progesterone displayed an additive effect on FasL expression compared with that observed with estradiol alone (Fig. 4c).
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In separate experiments, endometrial stromal cells were also incubated with estradiol and progesterone. FasL expression was observed in untreated endometrial stromal cells (Fig. 4d). Similar to that in endometrial glandular cells, FasL expression was also up-regulated by estradiol in stromal cells. Although progesterone had a minimal effect alone, when combined with estradiol, these hormones had an additive effect to stimulate FasL protein expression (Fig. 4d).
DISCUSSION
Differentiation and apoptosis of stromal and glandular cells during the decidualization of the receptive endometrium are crucial for the controlled invasion of trophoblasts and their intimate contact with maternal blood vessels. The regulation of apoptosis in the receptive endometrium by either intrinsic (maternal) or extrinsic (fetoplacental) signals is not yet completely understood.
Apoptosis in the human endometrium was first described by Hopwood [20] mainly in glandular cells of the late secretory, premenstrual, and menstrual phases and, to a lesser extent, in the proliferative phase. Various investigators have reported apoptosis of glandular cells in human endometrium and have focused on the role of apoptosis in the onset of menstruation and on regulation of the endometrial cycle [21–23]. Recently, apoptosis of glandular cells was detected to peak just at the time of the implantation window [5], suggesting a role for glandular apoptosis in human implantation. Our results suggest that FasL has a cycle-dependent expression in human endometrium and is expressed in both glandular and stromal cells. Relatively higher expression of this protein during the secretory phase compared with the proliferative phase goes along with the increased rate of apoptotic cell death observed at the mid-secretory phase. In this study we have shown that stromal cells as well as glandular cells express FasL in vivo and in vitro. To the best of our knowledge, this is the first report showing that endometrial stromal cells express FasL. This implies that stromal cells could also take part in maternal immunotolerance as an intrinsic signal. The stronger FasL immunoreactivity of stromal and glandular cells in the functional layer of the endometrium compared with the basal layer during the secretory phase is also significant because the initiation of decidualization occurs in the functional endometrium, where the blastocyst implants.
In this study we tested the hypothesis that estradiol and progesterone could regulate FasL expression in human endometrial glandular and stromal cells. We did not measure the endogenous estrogen and progesterone levels to directly assess their effect on FasL expression. On the other hand, we verified menstrual cycle day information by histological examination of the endometrium. Because apoptosis may contribute to two crucial events during early pregnancy (i.e., control of trophoblastic invasion and maternal immunotolerance to the embryo [4]), our results suggest that the increase in the apoptosis of glandular and stromal cells during the implantation window may be related to the effect of estrogen, progesterone, or both on FasL expression. The regulation of apoptosis in the receptive endometrium by extrinsic (fetoplacental) signals has also been suggested recently [24]. The human blastocyst induces a paracrine apoptotic reaction in human endometrial epithelial cells. Fas-FasL interaction between the apical surface of endometrial epithelial cells and the trophectoderm is proposed as a mechanism for invasion of the luminal epithelium and stroma. The maternal hormonal milieu (intrinsic) and fetoplacental (extrinsic) factors may have a synchronous effect on apoptotic cell death in the receptive endometrium during implantation and invasion.
Up-regulation of FasL by estradiol and progesterone in human endometrium could serve several roles in implantation. One potential role is the induction of apoptosis in activated cytotoxic T lymphocytes, which thus allows local immunotolerance. Another role would be the induction of glandular and stromal cell apoptosis, which allows trophoblastic invasion into the endometrium. Recent studies have demonstrated the FasL expression in human trophoblasts and have suggested a role in the apoptosis of maternal T lymphocytes, thereby allowing maternal immunotolerance to pregnancy [10, 11, 25]. Immunotolerance at the maternal-fetal interface was suggested to be similar to the immune privilege around Sertoli cells of the testis [8] and cornea [9]. Tumor escape from immunologic rejection in colon cancer [26], hepatocellular carcinoma [17], and melanoma [27] are also attributable to the apoptosis of activated T lymphocytes. A similar mechanism was introduced by a successful cotransplantation of pancreatic islet cells and myoblasts transfected with FasL cDNA into donor mice of a different strain to prevent immune rejection [28]. Activation of T lymphocytes by foreign antigens induces the expression of Fas, which upon binding to FasL, initiates a cascade of the apoptotic pathway that eliminates lymphocytes and suppresses the immune response [29, 30].
Besides FasL expression, we have also observed the expression of its receptor, Fas, on both endometrial stromal and glandular cells. Fas-FasL interaction on the same cell is also suggested as a possible autocrine mechanism of cell death [1]. The expression of both Fas and FasL on cytotrophoblasts and amnion epithelial cells of term fetal membranes is proposed as the self-regulatory mechanism of apoptosis at these sites [31]. Autocrine induction of apoptosis in glandular and stromal cells may be one of the mechanisms in the endometrium for a successful implantation and the controlled invasion of trophoblasts.
Regulation of apoptosis involves a complex set of events via interaction of several genes with stimulatory and inhibitory effects on cell death. There are also interactions between these regulatory genes as has been observed between the antiapoptotic gene Bcl-2 and the apoptotic Fas-FasL system. Bcl-2 inhibits Fas-mediated apoptosis by inactivating the interleukin-converting enzyme (ICE)-like protease of the Fas-FasL apoptotic pathway [32]. Our data on estradiol- and progesterone-mediated up-regulation of FasL expression in endometrial stromal and glandular cells suggest a novel mode of action for these hormones to modulate apoptosis regulatory genes and to thus contribute to successful implantation.
In conclusion, we have shown a cycle-dependent regulation of FasL expression in human endometrium, and demonstrated that FasL is up-regulated by estradiol and progesterone in endometrial stromal and glandular cells. We speculate that modulation of FasL by the maternal hormonal milieu may contribute to the immune privilege around the trophoblasts by inducing apoptosis in activated T lymphocytes and by inducing autocrine apoptosis of glandular and stromal cells that may contribute to a controlled trophoblastic invasion in human endometrium.
ACKNOWLEDGMENTS
The authors acknowledge the technical contributions of Drs. Junhui Zhang and Figen Koseoglu.
FOOTNOTES
First decision: 16 January 2001.
1 U.A.K. is supported by a training grant from the Turkish Scientific and Technical Research Council (TUBITAK). 
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
Accepted: May 7, 2001.
Received: November 27, 2000.
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