Molecular Human Reproduction, Vol. 5, No. 6, 554-558,
June 1999
© 1999 European Society of Human Reproduction and Embryology
Rapid down-regulation of CD63 transcription by progesterone in human endometrial stromal cells
Department of Obstetrics and Gynecology, Kansai Medical University, Moriguchi 570-8507, Japan
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Abstract |
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Differentiation of endometrial stromal cells (decidualization) plays a crucial role in embryo implantation and maintenance of pregnancy. While progesterone is a key factor in regulating endometrial cell decidualization, the molecular mechanisms remain unclear. In the present study, we investigated the effect of gene transcription in human endometrial stromal cells (ESC) by progesterone, oestrogen or vehicle using the polymerase chain reaction-based differential display methodology. A transcript which is down-regulated by progesterone, but not by vehicle and oestrogen, was identified from a differential display band and the progesterone sensitivity of its expression was verified in Northern blot analysis. The level of the gene expression in progesterone-treated ESC was ~60% of that in the vehicle- and oestrogen-treated ESC. This cDNA was revealed to be human CD63 antigen, a recently identified member of the transmembrane 4 superfamily. The inhibitory effect of progesterone is observed within 30 min after hormone treatment. In human endometrium, CD63 mRNA levels were significantly decreased (P < 0.05) during the secretory phase compared with levels during the proliferative phase. This down-regulation of CD63 in vivo elevated levels of progesterone in the secretory phase. These results suggest that CD63 transcription is down-regulated by progesterone in human endometrium.
CD63/differential display/endometrial stromal cell/endometrium/progesterone
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Introduction |
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In humans, the endometrium has a biological role in achieving successful implantation through secretory changes in the glandular epithelium and decidual changes in the stromal cells. The endometrium undergoes remarkable cyclic growth and regeneration in response to the female sex steroids oestrogen and progesterone. Progesterone has a central role in reproduction, being involved in ovulation, implantation, and pregnancy. If fertilization occurs, high circulating progesterone levels are important not only for facilitating implantation, but also for maintaining pregnancy by stimulating uterine growth (Clarke and Sutherland, 1990
; Graham and Clarke, 1997). The physiological effects of progesterone are known to be mediated initially by a specific intracellular protein termed the progesterone receptor (PR) (Truss and Beato, 1993; Tsai and O'Malley, 1994). The recent description of a mouse model carrying a null mutation of the PR gene has displayed defects in all reproductive tissues. These included an inability to ovulate and decidualize, uterine hyperplasia and inflammation (Lydon et al., 1995). However, most of the downstream molecular and cellular mechanisms by which progesterone exerts these effects have not been clarified.
Recently, an in-vitro model of human decidualization has been developed. In this model, human endometrial stromal cells (ESC) cultured in the presence of progesterone undergo morphological differentiation and produce decidual proteins such as prolactin and insulin-like growth factor binding protein-1 (Irwin et al., 1991; Tabanelli et al., 1992; Gao and Tseng, 1996). We and others have used this model and found that progesterone enhanced macrophage colony-stimulating factor, tissue factor, plasminogen activator inhibitor type 1, tissue inhibitor of metalloproteinase (TIMP), and tissue transglutaminase type II (TGase) (Schatz and Lockwood, 1993; Hatayama et al., 1994; Higuchi et al., 1995; Fujimoto et al., 1996; Zhang and Salamonsen, 1997; Krikun et al., 1998). In this present study, we have screened for mRNA that is differentially regulated by progesterone in ESC using differential display techniques (Liang and Pardee, 1992). This has resulted in the identification of a new down-regulated mRNA by progesterone and it has been revealed to be human CD63 antigen, a member of the transmembrane 4 superfamily.
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Materials and methods |
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Specimens
Human endometrial tissues were obtained from 10 patients, aged 38–49 years, with regular menstrual cycles, who underwent hysterectomies for the treatment of myoma uteri without hormonal therapy. A portion of each endometrial specimen was examined histologically and dated according to criteria of Noyes et al. (Noyes et al., 1950
). Informed consent was obtained from all patients. The tissue specimens from which RNA was extracted were immediately frozen in liquid nitrogen and stored at –80°C.
Cell cultures
ESC were purified from the proliferative phase endometrium and cultured as described previously (Imai et al., 1992; Hatayama et al., 1994). Briefly, tissue samples were washed with Dulbecco's modified Eagle's medium (DMEM)/F-12 medium (Gibco BRL, Grand Island, NY, USA) and minced into small pieces of <1 mm3. The tissues were then incubated for 2 h at 37°C in DMEM/F-12 medium containing 1 mg/ml collagenase (Wako Pure Chemical Co. Ltd, Osaka, Japan) and 0.005% deoxyribonuclease type I (Boehringer Mannheim GmbH, Mannheim, Germany). After subsequent pipetting, the cell suspension was diluted with 2 volumes DMEM/F-12 medium and placed in a centrifugation tube (Corning Glass Works, Corning, NY, USA), where it remained upright for 10 min at unit gravity. The supernatant, excluding the lowermost 2 ml, was transferred into a new tube to collect suspended single cells. After repeating this procedure several times, the cell suspension was washed three times and used as a source of ESC. The viability, determined by dye exclusion, was 
90%. Two million viable ESC were cultured in 75 cm2 flasks in DMEM/F-12 medium supplemented with 10% FCS (HyClone, Logan, UT, USA), 100 IU/ml penicillin, and 100 µg/ml streptomycin (Gibco BRL) at 37°C in humidified atmosphere of 5% CO2 in air. After ESC from passages 1–2 were nearly confluent (cultures were maintained for 1–2 weeks), they were washed and medium was replaced with progesterone (10–6 mol/l) (Sigma Chemical Co., St Louis, MO, USA), oestrogen (17 ß-oestradiol; 10–8 mol/l) (Wako) or ethanol as vehicle control. The culture media were changed every 3 days.
RNA extraction and Northern blotting
Total RNA was prepared from frozen tissues and cultured cells by the acid guanidinium–phenol–chloroform method using TRIzol Reagent (Gibco BRL). Total RNA (20 µg) was separated in a 1.2% formaldehyde gel and transferred to Hybond-N+ nylon membrane (Amersham Corp., Arlington Heights, IL, USA). The probe was labelled by multiprime DNA labelling system (Amersham). The human decidual prolactin probe was prepared as described previously (Hatayama et al., 1994) and the human glyceraldehyde 3-phosphate dehydrogenase (GAPDH) probe was kindly provided by Dr Nishizawa (Kansai Medical University). Hybridization was at 42°C for 18 h in 5xstandard saline-phosphate-EDTA (SSPE)/5xDenhardt's solution/50% formamide/0.5% sodium dodecyl sulphate (SDS)/100 µg/ml salmon sperm DNA. The filter was washed at room temperature in 2x standard saline citrate (SSC)/0.1% SDS, followed by 0.1xSSC/0.1% SDS at 50°C, and then autoradiographed. The membrane was stripped and rehybridized with the human GAPDH probe. The mRNA levels were calculated after normalization to GAPDH mRNA expression on the basis of the hybridized signal as measured in a BAS 2000 Bioimage Analyzer (Fujix, Tokyo, Japan).
Differential display
For the first step of the procedure (reverse transcription), total RNA (2.5 µg) were mixed with 50 pmol of the anchored oligo-dT primer (5'-GT14MN-3') (M = the mixture of A, C and G; N = one of A, C, G or T) in 10 µl of DEPC-treated water, heated at 70°C for 10 min and chilled by immersing the tube in ice-water. To this solution, 10 µl of 2xRT solution (1xRT solution = 20 mM Tris–HCl, pH 8.4, 50 mM KCl, 2.5 mM MgCl2, 10 mM DTT, 0.1 mg/ml BSA and 0.5 mM each dNTP) containing 200 units of Superscript II reverse transcriptase (Gibco BRL) was added and incubated at 25°C for 10 min and at 42°C for 50 min. Following the incubation at 90°C for 5 min, the reaction mixture was diluted 5-fold by addition of 80 µl of TE (10 mM Tris–HCl, pH 8.0, 1 mM EDTA). For the second step [polymerase chain reaction (PCR) amplification], 2 µl cDNA solution was used for PCR amplification in 20 µl solution containing 5 pmol each appropriate 32P-labelled oligo-dT primer, 10 pmol of one of 20 arbitrary 10-mer primers (Operon Technologies, CA, USA), 10 mM Tris–HCl, pH 8.3, 50 mM KCl, 1.5 mM MgCl2, 50 µM each dNTP and 1 unit Taq polymerase (Takara Co. Ltd, Ohtsu, Japan). The thermocycling was at 94°C for 3 min, 40°C for 5 min, and 72°C for 5 min followed by 25 cycles of 95°C for 15 s, 40°C for 2 min, and 72°C for 1 min. The PCR reaction products were separated on 6% polyacrylamide/7 mol/l urea DNA sequencing gel and visualized by autoradiography. Bands of interest were eluted from the gel and eluted DNA subjected to further round of PCR. PCR products were purified on agarose gel electrophoresis and eluted DNA bands cleaned using a commercial DNA purification kit (Bio 101, Inc., Vista, CA, USA). DNA was cloned into pCR 2.1 vector system (Invitrogen Corp., Carlsbad, CA, USA). Plasmid preparations were prepared using a commercial kit following the manufacturer's instructions (Promega Corp., Madison, WI, USA) and DNA sequencing performed on a ABI PRISM 310 Genetic Analyzer (Perkin-Elmer, Norwalk, CT, USA).
Statistical analysis
Data are expressed as mean ± SD. Differences among data sets were evaluated by Wilcoxon's test (non-paired). A value of P < 0.05 was considered statistically significant.
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Results |
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mRNA for differential display was isolated from ESC which were treated with progesterone, oestrogen, or vehicle. The cDNA synthesis was carried out with each of the anchored oligo-dT primer (5'-GT14MN-3') (M = the mixture of A, C and G; N = one of A, C, G or T) and PCR amplification with the corresponding anchored oligo-dT primer and each of 20 different 10-mer primers of arbitrary sequence. Figure 1A
shows an example of the differential display patterns obtained. Differential display yielded one band reduced in ESC in the presence of progesterone as compared with oestrogen and vehicle (Figure 1A, arrow). This result was confirmed by three separate experiments. The differentially expressed band was eluted from the gel, cloned, sequenced, and was found to be 214 nucleotides long. This cDNA was then used in Northern blot analysis to ascertain regulation of ESC. The level of the gene expression in progesterone-treated ESC was ~60% of that in the vehicle- and oestrogen-treated ESC (Figure 1B). Comparison of the cDNA with the European Molecular Biology Laboratory (EMBL)/GenBank databases showed that it had 99% homology with the published sequence from CD63 mRNA from nucleotides 662 to 876 (Metzelaar et al., 1991a). To determine whether the effect of progesterone on CD63 mRNA levels was dependent on time, Northern blot analyses were performed using ESC at various times after progesterone treatment. Figure 2 shows patterns of progesterone regulation of CD63 mRNA in ESC alongside regulation patterns for the established progesterone-regulated prolactin mRNA and control unregulated GAPDH mRNA. The induction of prolactin mRNA was detected after 7 days of culture with progesterone. The CD63 mRNA level decreased within 30 min after progesterone treatment and there was a rebound in the CD63 expression on day 7 (Figure 2). In the absence of progesterone, no change in CD63 mRNA levels was observed during the same culture period (data not shown). As progesterone was shown to reduce CD63 in ESC in vitro, we compared CD63 mRNA levels in human endometrium between the proliferative and secretory phases. CD63 mRNA levels during the secretory phase were significantly lower than those during the proliferative phase (Figure 3). Since progesterone levels are known to be higher in the secretory phase than in the proliferative phase, it is possible that the reduced levels of CD63 mRNA are the result of progesterone activity in vivo.
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Discussion |
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The steroid hormone progesterone is a key modulator of the cellular processes associated with the maintenance and development of female reproductive function (Clarke and Sutherland, 1990
; Graham and Clarke, 1997). Indeed, progesterone restrains endometrial tissue breakdown by blocking the secretion and activation of matrix metalloproteinases (MMP), the family of enzymes responsible for degradation of components of the extracellular matrix (Marbaix et al., 1992). The biological activity of this hormone is mediated by PR located in target cell nuclei. PR are ligand-regulated sequence-specific transcription factors that may activate or repress gene expression. Progesterone gene transcription is mediated by the binding of progesterone response elements (Truss and Beato, 1993; Tsai and O'Malley, 1994). Previously, we have demonstrated the induction of macrophage colony-stimulating factor (M-CSF) and TIMP-3 mRNA in ESC after 3 and 6 days, respectively, of culture with progesterone (Hatayama et al., 1994; Higuchi et al., 1995). However, it has been shown that TIMP-3 is also produced by non-decidualized ESC and that there is some increase with decidualization (Zhang and Salamonsen 1997). The induction of TGase mRNA was observed as early as 6 h after initiation of culture (Fujimoto et al., 1996). In the present study, we have isolated a new regulated gene by progesterone from differential display method (Figure 1
) and demonstrated that CD63 is rapidly down-regulated by progesterone in ESC (Figure 2).
CD63 belongs to the newly identified transmembrane 4 superfamily of membrane proteins including CD9, CD37, CD53, CD81 and CD82 (Maecker et al., 1997). CD63 was used as a marker of platelet activation (Nieuwenhuis et al., 1987) and identified as the human melanoma-associated antigen ME491 (Metzelaar et al., 1991a). Although the function of CD63 is largely unknown, it is one of the major lysosomal membrane proteins (Metzelaar et al., 1991b) and has been suggested to have a role in signal transduction through PI4-kinase and on substrates associated with ß1 integrins (Skubitz et al., 1996; Berditchevski et al., 1997; Radford et al., 1997). CD63 was described originally as a marker for the early stages of melanoma progression since it was highly expressed in radial growth-phase primary melanomas, but weaker or absent in vertical growth-phase and metastatic melanomas, and absent on normal melanocytes (Hotta et al., 1988; Kondoh et al., 1993).
What is the underlying mechanism that explains the inhibition of CD63 transcription by progesterone treatment in ESC? In CD63, the promoter region is G–C rich and contains three transcription initiation sites, as well as potential binding sites for the transcription factors AP-1, Sp1, and ETF (Hotta et al., 1992). Deletion mutant analysis of the 5'-flanking sequence suggests that a potential binding site for AP-1 plays an important role in positively regulating CD63 gene expression (Hotta et al., 1992). AP-1 is a sequence-specific transcription factor composed of either homo- or heterodimers among members within the Jun family or among proteins of the Jun and Fos families (Angel and Karin, 1991; Whitmarsh and Davis, 1996). AP-1 transcriptional activity is modulated by growth factors, cytokines, and tumour promoters that activate protein kinase C (Angel and Karin, 1991). Several groups have recently reported extensive cross-talk between AP-1 proteins and nuclear receptors. Though inhibition of AP-1 activity was initially described for the glucocorticoid receptor, other members of the nuclear receptor superfamily, including retinoic acid, androgen and thyroid hormone receptors, show the same activity (Jonat et al., 1990; Schüle et al., 1990; Saatcioglu et al., 1994; Mangelsdorf et al., 1995). The activated PR-mediated inhibition of AP-1 activity was described previously in HeLa and endometrial adenocarcinoma cells (Shemshedini et al., 1991; Bamberger et al., 1996). However, the oestrogen receptor clearly behaved differently from the other receptors and had a stimulatory effect in most systems, including human endometrial cells (Hyder et al., 1995; Webb et al., 1995; Bamberger et al., 1996). Thus, the decrease of CD63 transcription may be caused by the activation of PR which affects AP-1 transcriptional activity in ESC. However, it is possible that unidentified progesterone response element-like sequences are involved in progesterone-mediated down-regulation of CD63 transcription.
We have revealed the expression of CD63 mRNA in ESC. Our present study relies on a small number of the sample size due to the limitation of clinical materials, but we have shown the statistically significant decrease of CD63 mRNA level in secretory phase endometrium, when serum progesterone levels are known to be elevated (Figure 3). Although the biological significance of the decrease in CD63 in human endometrium by progesterone is unknown, the regulation of CD63 by progesterone may have a role of proliferation and differentiation in human endometrium. Further studies in vivo and in vitro are required in order to clarify the physiological consequences of progesterone-induced decrease of CD63 in human endometrium.
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Acknowledgments |
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We would like to thank Dr T.Shimizu for helping with differential display analysis; M.Imai for excellent technical assistance; N.Sugie and Y.Morita for the editorial assistance. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (#07457386).
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Notes |
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1 To whom correspondence should be addressed
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Submitted on October 22, 1998; accepted on February 23, 1999.
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