Molecular Human Reproduction, Vol. 6, No. 1, 75-80,
January 2000
© 2000 European Society of Human Reproduction and Embryology
Uterus and pregnancy |
Expression of interleukin-15 in human endometrium and decidua
Department of Obstetrics and Gynecology, Kansai Medical University, Moriguchi 570-8507, Japan
Abstract
In human endometrium, cytokines and growth factors that vary periodically during the menstrual cycles have been suggested to play various roles in uterine function. In the present study, differential gene expression in human endometrium between the proliferative and the secretory phases was investigated by using a human cDNA expression array system. Human interleukin (IL)-15 was identified as an up-regulated transcription product during the secretory phase, in comparison with the proliferative phase, and therefore its expression in human uterus was examined by Northern blot analysis. In human endometrium, expression of IL-15 mRNA significantly increased during the secretory phase compared with the proliferative phase (P < 0.01). The most abundant expression of IL-15 mRNA during the menstrual cycle was observed in the midsecretory phase. In the first trimester pregnancy, the expression of IL-15 mRNA in the decidua was significantly higher than that in the chorionic villi (P < 0.01). By using an in-vitro decidualization with human endometrial stromal cells, it was demonstrated that the expression of IL-15 mRNA is up-regulated during progesterone-induced decidualization. These results suggest that IL-15 plays a role in uterine function during pregnancy, as well as during the menstrual cycle.
chorion/decidua/decidualization/endometrium/IL-15
Introduction
Human 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 consists not only of epithelial cells and stromal fibroblasts, but also of vascular endothelial cells, macrophages, and lymphoid cells. Orchestrated responses to ovarian steroid hormones by all of these various cell types are necessary for successful implantation and placentation. In addition, another group of local autocrine and paracrine molecules, namely, cytokines, integrin adhesion molecules, and proteinases involved in cell invasion, also play an essential role in this process (Cross et al., 1994
; Lessey, 1998; Shiokawa et al., 1998). In the mice model, growth factors and cytokines [especially macrophage colony-stimulating factor (M-CSF), leukaemia inhibitory factor (LIF), interleukin (IL)-1, and IL-11] and their specific receptors are adequately distributed throughout the endometrium and blastocyst (Pollard et al., 1991; Stewart et al., 1992; Simón, et al., 1994; Bilinski et al., 1998; Robb et al., 1998). Previously, it has been demonstrated that some cytokines including M-CSF, stem cell factor and LIF are expressed in human endometrium (Hatayama et al., 1994; Kanzaki et al., 1994; Kojima et al., 1994). 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). Studies using this model have found that progesterone enhanced M-CSF, tissue factor, plasminogen activator inhibitor type 1, tissue inhibitor of metalloproteinase and tissue transglutaminase type II (Schatz and Lockwood, 1993; Hatayama et al., 1994; Higuchi et al., 1995; Fujimoto et al., 1996; Zhang and Salamonsen, 1997; Krikun et al., 1998). These findings suggest close interaction between the immune and endocrine systems in human endometrium. However, the underlying mechanisms and the molecular components involved have not been identified as yet in human endometrium.
Genes that vary periodically during the menstrual cycles have been suggested to play various roles in human endometrium. Thus, identification and characterization of changes in the gene expression during the menstrual cycles leads to a better understanding of blastocyst implantation and/ or early placental development. Several molecular biology techniques of differential library hybridization, suppression subtractive hybridization, and polymerase chain reaction-based differential display have been utilized to isolate and characterize differentially expressed genes (Liang and Pardee, 1992; Diatchenko et al., 1996). In a recent study the technique of differential display was used to isolate progesterone-regulated gene in ESC (Okada et al., 1999). Here, we investigated the differential gene expression between the proliferative and the secretory phases by using a human cDNA expression array system.
Materials and methods
Specimens
Human endometrial tissues were obtained from 34 patients, aged 35–48 years, with regular menstrual cycles, who underwent hysterectomies for the treatment of myoma uteri and pelvic relaxation without hormonal therapy. A portion of each endometrial specimen was examined histologically and dated according to established criteria (Noyes et al., 1950). First trimester human decidua (n = 6) and chorionic tissue sample (n = 5) were obtained from patients who had undergone legal abortions. 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 (DNase) 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 die exclusion, was 
90%. Two million viability ESC were cultured in 75 cm2 flasks in DMEM/F-12 medium supplemented with 10% fetal calf serum (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 and 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) 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). Human S26 probe, the mRNA-binding human ribosomal protein RNA, was prepared as described previously (Hatayama et al., 1994). 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 filters were washed at room temperature in 2xstandard saline citrate (SSC)/0.1% SDS, following by 0.1xSSC/0.1% SDS at 50°C, and then autoradiographed. The membranes were deprobed and rehybridized with the human S26 probe as an internal control, because its expression is virtually constant in many tissues (Vincent et al., 1993). The amounts of mRNA were calculated after normalization to S26 mRNA expression on the basis of the hybridized signal as measured in a BAS 2000 Bioimage Analyzer (Fujix, Tokyo, Japan).
cDNA expression array
For analysing different gene expression between the proliferative and the secretory phase in human endometrium, two Atlas human cDNA expression array membranes (Clontech, Palo Alto, CA, USA) were used. The materials provided with the kit were used and the recommended protocol was followed for all steps. Briefly, total RNA (20 µg) of human endometrium from the proliferative and from the secretory phases were treated with 5 µl of DNase I (Boehringer Mannheim) at 37°C for 1 h. RNA was then precipitated at –80°C for 30 min using 0.1 volume of 3 mol/l sodium acetate pH 5.2 and 2.5 volume of 100% ethanol and converted into 32P-labelled first strand cDNA by means of Superscript II reverse transcriptase (Gibco BRL). Unincorporated 32P-labelled nucleotides were removed by CHROMA SPIN-200 column chromatography (Clontech). After prehybridization [30 min at 68°C in ExpressHyb (Clontech)], the heat-denatured probes were hybridized to Atlas human cDNA expression array membranes for 18 h at 68°C. The membranes were washed at room temperature in 2xSSC/1% SDS for 60 min, followed by 0.1xSSC/0.5% SDS at 68°C for 40 min, and then autoradiographed.
Reverse transcription–polymerase chain reaction (RT–PCR)
Total RNA (2 µg) was reverse transcribed using the Superscript preamplification system (Gibco BRL). One-tenth of the cDNA obtained was amplified in a 100 µl reaction, using each 1 µmol/l primers, 10 mmol/l Tris–HCl, pH 8.3, 50 mmol/l KCl, 1.5 mmol/l MgCl2, 50 µmol/l each dNTP and 2.5 unit Taq polymerase (Takara Co. Ltd., Ohtsu, Japan). The PCR primers were as followed: IL-15 (Grabstein et al., 1994), sense strand, 5'-GAGAATTTCGAAACCACATTTGAG-3'; anti-sense strand, 5'-AGAAGTGTTGATGAACATTTGGAC-3'; EPS (epidermal growth factor pathway substrate) 15 (Wong et al., 1994), sense strand, 5'-TTGGAGGTGGATTTGCTGACTTCA-3'; anti-sense strand, 5'-AGATTTGCTGAGTGCAATAGCCAG-3'. The thermocycling was at 94°C for 2 min followed by 35 cycles of 94°C for 15 s, 50°C for 30 s, and 68°C for 2 min. 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 an ABI PRISM 310 Genetic Analyzer (Perkin–Elmer, Norwalk, CT, USA). The inserts were purified and used as human IL-15 and EPS15 probes in Northern blot analyses.
Statistical analysis
Data are expressed as mean ± SD. Differences among data sets were evaluated by Wilcoxon's test (non-paired). P < 0.05 was considered statistically significant.
Results
The technique of differential hybridization of human cDNA expression array was used to identify differences in the expression pattern of genes between the proliferative and the secretory phases in human endometrium. Figure 1A shows examples of the expression arrays obtained. EPS15 genes were expressed in similar amounts in both the proliferative and the secretory phases. EPS15 encoded a protein of 140–150 kDa that was phosphorylated on tyrosine following activation of epidermal growth factor (EGF) receptor and platelet-derived growth factor receptor (Fazioli et al., 1993). One of the most prominent changes observed was an increase of IL-15 mRNA in the secretory phase. IL-15 is a novel cytokine with functions similar to those of IL-2 in the cell-mediated immune response (Grabstein et al., 1994). To determine whether EPS15 and IL-15 mRNA were expressed in human endometrium, Northern blot analysis was used. As shown in Figure 1B, EPS15 transcripts of 5.1 kilobases (kb) were detected in similar amounts in both the proliferative and the secretory phases. IL-15 transcripts of 1.5 kb increased in the secretory phase compared with the proliferative phase. The existence of two isoforms of IL-15 was described previously (Meazza et al., 1996; Onu et al., 1997). For human endometrium two bands of 486 and 605 bp were observed that corresponded to the two described splice isoforms by RT–PCR (data not shown). The endometrium expressed mostly the smaller product. To monitor the expression of IL-15 mRNA in human endometrium during the menstrual cycle, RNA isolated from human endometrium was analysed for the presence of IL-15 by Northern blot analysis (Figure 2). The amount of IL-15 mRNA was low in samples obtained in the proliferative phase. In the secretory phase, the amounts increased dramatically. IL-15 mRNA reached the highest value in the midsecretory phase. Overall, expression in the secretory phase was 4- to 5-fold higher than in the proliferative phase (P < 0.01). Although human placenta is reported as an important source of IL-15 (Grabstein et al., 1994), IL-15 mRNA expression in the first trimester of pregnancy has not been specified. IL-15 gene expression of the decidua and the chorionic villi in the first trimester was investigated by Northern blot analysis (Figure 3). The amount of IL-15 mRNA in the decidua was 8.7 ± 2.2-fold higher than that in the chorionic villi (P < 0.01). By using an in-vitro decidualization, it was possible to determine whether expression of IL-15 mRNA was regulated in ESC during the process of decidualization by progesterone. Northern blot analysis was performed using ESC at various times after progesterone treatment. Figure 4 shows patterns of progesterone regulation of IL-15 mRNA in ESC alongside control unregulated S26 mRNA. IL-15 mRNA significantly increased in the presence of progesterone after 7 days. The induction of prolactin mRNA was detected after 7 days of culture with progesterone (data not shown). In the absence of progesterone, no change in the amount of IL-15 mRNA was observed during the same culture period (data not shown). This result was confirmed by three separate experiments.
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Discussion
In this study, it was demonstrated that the expression of IL-15 mRNA significantly increases during the secretory phase compared with the proliferative phase by using human cDNA expression array. IL-15 is a novel cytokine that has recently been cloned and sequenced from simian kidney epithelial cells CV-1/EBNA (Grabstein et al., 1994) and from human adult T cell leukaemia cell line HuT-102 (Bamford et al., 1994). It is a member of the four 
helix bundle cytokine family, which binds to and induces signalling through the IL-2 receptor ß and 
chains (Tagaya et al., 1996). IL-15 shares a number of biological activities with IL-2. IL-15 acts as a T cell stimulant and plays a pivotal role in cell-mediated immunity by activating T cell proliferation and B cell antibody production, and by promoting natural killer (NK) cell cytotoxicity (Carson et al., 1994; Armitage et al., 1995). Unlike IL-2, IL-15 is not produced by activated T-cells; however, the expression of mRNA for IL-15 has been seen in many other cell types (Grabstein et al., 1994). The broad expression of mRNA encoding IL-15 compared with the expression of IL-2 suggests that IL-15 has activities beyond the immune system. For example, IL-15 stimulates muscle protein accretion in cultured skeletal muscle fibres (Quinn et al., 1995) and the differentiation of osteoclast progenitors into pre-osteoclasts (Ogata et al., 1999). IL-15 also enhances the invasion and migration of cytotrophoblastic (JEG-3) cells in vitro (Zygmunt et al., 1998). IL-15 mRNA is expressed in most tissues thus far examined, and the highest amounts observed are in skeletal muscle and placenta, with smaller amounts found in heart, kidney, lung, liver, and the dermal layers of skin (Grabstein et al., 1994). However, IL-15 transcript expression has not been described in human endometrium. Herein, it was demonstrated that IL-15 mRNA can be detected in human endometrium. Furthermore, the most abundant IL-15 mRNA level during the menstrual cycle was observed in the midsecretory phase (Figure 2
). However, the cellular origin of the IL-15 mRNA was not confirmed in endometrial samples obtained throughout the menstrual cycle, because the endometrium consists of epithelial cells, stromal fibroblasts, and leukocytes. Next, it was demonstrated that expression of IL-15 mRNA in ESC increased during the process of decidualization by progesterone (Figure 4). Therefore, it is possible that the likely source of IL-15 mRNA in the midsecretory phase is the epithelial cells and/or the leukocytes.
These findings suggest the importance of IL-15 during the secretory phase and early pregnancy, when progesterone from corpus luteum affects the uterus. Indeed, it is suggested that IL-15 is involved in regulating the differentiation of granulated metrial gland (GMG) cells during mouse pregnancy (Ye et al., 1996; Allen and Nilsen-Hamilton, 1998). GMG cells belong to the NK cell lineage and have been identified in human as uterine NK (uNK) cells (King and Loke, 1991; Whitelaw and Croy, 1996). uNK cells are present in large numbers in human decidua. These cells are characterized by the marked expression of the NK cell marker CD56, despite the absence of CD16, another NK cell marker. Such CD16– CD56bright NK cells differ from the CD16+ CD56dim NK cells that constitute a large proportion of NK cells in peripheral blood (King and Loke, 1991; Nishikawa et al., 1991). In non-pregnant women, few CD16– CD56bright NK cells are apparent in the endometrium during the proliferative phase, but these cells increase in number during the secretory phase and they account for 70–80% of all lymphocytes in the early stages of pregnancy (King and Loke, 1991; Nishikawa et al., 1991; King et al., 1998). Furthermore, CD16– CD56bright NK cells proliferate in the endometrium during the secretory phase and in early decidua, as demonstrated by staining for the proliferation marker Ki-67 (Pace et al., 1989; Klentzeris et al., 1992; King et al., 1998). These cells are thought to play an important role in the maintenance of pregnancy. Although the specific functions of CD16– CD56bright NK cells are unclear, they may regulate trophoblast invasion into the decidua. Indeed, trophoblast killing by murine and human uNK cells has been reported (Stewart and Mukhtar, 1988; King and Loke, 1990). Other previously proposed uNK cell functions include lysis of virus-infected cells present in the uterus and placenta, nutritive function, and cytokine production (Tarachand, 1986; Whitelaw and Croy, 1996). IL-15 has been shown to stimulate proliferation of human NK cells and cytokine production by these cells (Carson et al., 1994). IL-15 induces strong proliferative responses in the CD56bright subset of human NK cells, which represents ~1% of peripheral blood lymphocytes and 10% of human NK cells (Carson et al., 1994). Therefore, increased IL-15 mRNA expression in human secretory endometrium and decidua implies an important role of this cytokine in the regulation of CD16- CD56bright NK cells in human endometrium.
The IL-15 receptor contains the ß and chain of IL-2 receptor and a recently identified specific chain (Anderson et al., 1995; Giri et al., 1995). We have also detected IL-15 receptors in decidua by Northern blot analysis (S. Okada et al., unpublished data). These findings are consistent with the notion that IL-15 acts through IL-15 receptors expressed on the endometrium at the time of implantation and/or early placental development. Further in-vivo and in-vitro studies are required in order to clarify the physiological consequences of increased IL-15 in human endometrium.
Acknowledgments
We would like to thank M.Imai for excellent technical assistance; and 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)
Notes
1 To whom correspondence should be addressed 
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Submitted on June 3, 1999; accepted on September 17, 1999.
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T. Nakamoto, H. Okada, T. Nakajima, A. Ikuta, K. Yasuda, and H. Kanzaki Progesterone induces the fibulin-1 expression in human endometrial stromal cells Hum. Reprod., June 1, 2005; 20(6): 1447 - 1455. [Abstract] [Full Text] [PDF]
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L. C. Kao, A. Germeyer, S. Tulac, S. Lobo, J. P. Yang, R. N. Taylor, K. Osteen, B. A. Lessey, and L. C. Giudice Expression Profiling of Endometrium from Women with Endometriosis Reveals Candidate Genes for Disease-Based Implantation Failure and Infertility Endocrinology, July 1, 2003; 144(7): 2870 - 2881. [Abstract] [Full Text] [PDF]
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F. Taniguchi, T. Harada, Y. Sakamoto, N. Yamauchi, S. Yoshida, T. Iwabe, and N. Terakawa Activation of Mitogen-Activated Protein Kinase Pathway by Keratinocyte Growth Factor or Fibroblast Growth Factor-10 Promotes Cell Proliferation in Human Endometrial Carcinoma Cells J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 773 - 780. [Abstract] [Full Text] [PDF]
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A. Arici, I. Matalliotakis, A. Goumenou, G. Koumantakis, S. Vassiliadis, B. Selam, and N. G. Mahutte Increased levels of interleukin-15 in the peritoneal fluid of women with endometriosis: inverse correlation with stage and depth of invasion Hum. Reprod., February 1, 2003; 18(2): 429 - 432. [Abstract] [Full Text] [PDF]
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K.-H. Chao, M.-Y. Wu, J.-H. Yang, S.-U. Chen, Y.-S. Yang, and H.-N. Ho Expression of the interleukin-2 receptor {alpha} (CD25) is selectively decreased on decidual CD4+ and CD8+ T lymphocytes in normal pregnancies Mol. Hum. Reprod., July 1, 2002; 8(7): 667 - 673. [Abstract] [Full Text] [PDF]
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L. C. Kao, S. Tulac, S. Lobo, B. Imani, J. P. Yang, A. Germeyer, K. Osteen, R. N. Taylor, B. A. Lessey, and L. C. Giudice Global Gene Profiling in Human Endometrium during the Window of Implantation Endocrinology, June 1, 2002; 143(6): 2119 - 2138. [Abstract] [Full Text] [PDF]
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O. Yoshino, Y. Osuga, K. Koga, O. Tsutsumi, T. Yano, T. Fujii, K. Kugu, M. Momoeda, T. Fujiwara, K. Tomita, et al. Evidence for the expression of interleukin (IL)-18, IL-18 receptor and IL-18 binding protein in the human endometrium Mol. Hum. Reprod., July 1, 2001; 7(7): 649 - 654. [Abstract] [Full Text] [PDF]
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H. Okada, T. Nakajima, T. Yoshimura, K. Yasuda, and H. Kanzaki The inhibitory effect of dienogest, a synthetic steroid, on the growth of human endometrial stromal cells in vitro Mol. Hum. Reprod., April 1, 2001; 7(4): 341 - 347. [Abstract] [Full Text] [PDF]
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R. Agarwal, A. Loganath, A.C. Roy, Y.C. Wong, and S.C. Ng Expression profiles of interleukin-15 in early and late gestational human placenta and in pre-eclamptic placenta Mol. Hum. Reprod., January 1, 2001; 7(1): 97 - 101. [Abstract] [Full Text] [PDF]
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H. Okada, T. Nakajima, M. Sanezumi, A. Ikuta, K. Yasuda, and H. Kanzaki Progesterone Enhances Interleukin-15 Production in Human Endometrial Stromal Cells in Vitro J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4765 - 4770. [Abstract] [Full Text]
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