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IL-15 Expression at Human Endometrium and Decidua

^a Department of Obstetrics and Gynecology and ^b Dynamic Pathology Research Institute, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan

ABSTRACT

A large number of natural killer (NK) cells appear in human uterine mucosa during the secretory phase and first trimester pregnancy. We investigated the expression of interleukin (IL)-15, a possible stimulator for these NK cells, in human endometrium and first trimester decidua. Semiquantitative reverse transcriptase-polymerase chain reaction revealed that IL-15 mRNA expression was stronger during the secretory phase and first trimester pregnancy than during the proliferative phase. Immunohistochemistry revealed that immunoreactivity for anti-IL-15 was higher during the secretory phase than it was during the proliferative phase. This was prominent in the perivascular stromal cells around invading spiral arteries during the mid- to late-secretory phase. In first trimester decidua, endothelial cells were also stained as strongly as stromal cells. A membrane-bound IL-15 molecule was detected on the surface of first trimester decidual cells by flow cytometry. Progesterone stimulated the release of soluble IL-15 in the supernatant of cultured decidual cells. These results suggest that IL-15 expression in human uterine mucosa corresponds to the fluctuation of uterine NK cells and that its production is hormonally controlled, especially by progesterone.

cytokines, female reproductive tract, reproductive immunology, uterus

INTRODUCTION

Several investigators have shown that lymphocytes are present in human uterine endometrium and decidua [1–3]. Throughout the menstrual cycle and first trimester, 70% to 80% of uterine mucosal lymphocytes are characteristic CD16–CD56++ large granular lymphocytes, whereas these lymphocytes comprise less than 1% of the lymphocyte population in peripheral blood [2, 4, 5]. Although these lymphocytes are phenotypically and morphologically classified as natural killer (NK) cells, they have less cytotoxicity than peripheral blood NK cells [2, 6]. Moreover, they proliferate [4, 7], activate in the mucosa [5], and produce cytokines such as leukemia inhibitory factor and macrophage-colony stimulating factor, which play important roles in implantation and placental growth [8–11].

The number of NK cells is low in the endometrium in the proliferative phase, but it increases during the mid-secretory phase. NK cells undergo apoptosis during the premenstrual period, but they survive in the first trimester decidua when pregnancy is successful [3]. These variations suggest that sex-steroid hormones are involved in the stimulation of uterine NK cells; however, these NK cells lack receptors for estrogen and progesterone [12, 13]. Interleukin (IL)-2 is known for its strong proliferating and activating function on uterine NK cells in vitro [2, 14, 15]. Despite the expression of high-affinity receptors for IL-2 composed of , ß and the common chain on uterine NK cells, it is difficult to detect IL-2 in nonpathologic human endometrium and decidua [8, 11, 16]. Another candidate, stem cell factor, cannot proliferate uterine NK cells in the absence of IL-2 [17]; thus, the mechanism controlling the proliferation and survival of uterine NK cells is not yet fully known.

Recently, the cytokine IL-15 was discovered [18]. Its molecular structure and biological function are similar to those of IL-2, but its sequence and tissue localization are quite different from those of IL-2. IL-15 can proliferate the entire lymphocyte population, including NK cells [18–20].

IL-15 receptor (R) also resembles IL-2R because it is composed of three subunits: IL-15R, the molecule binding site; IL-2Rß; and the common chain, which is the signal transduction site [21, 22]. These similarities between IL-2 and IL-15 suggest that IL-15 may be a potent effector of uterine NK cells. In this study, the expression, localization, and secretion of IL-15 in human endometrium and first trimester decidua were investigated.

MATERIALS AND METHODS

Samples

Endometrial tissues (15 in proliferative phase, 13 in secretory phase) were collected from women who underwent hysterectomy for leiomyoma or carcinoma in situ of the uterine cervix. Decidual tissues were obtained from 12 women who had undergone selective termination at 7–11 wk of gestation. Informed consent was obtained from the women before the operation, and this study was conducted in accordance with the Declaration of Helsinki guidelines.

Cell Preparation and Culture

All samples were washed several times in PBS (Takara, Shiga, Japan) to remove blood clots. A part of each sample was fixed overnight at 4°C in 4% paraformaldehyde (Nakarai, Kyoto, Japan) (in phosphate buffer, pH 7.3) for immunohistochemistry. The remaining tissue was used for cell culture, flow cytometry, and reverse transcriptase-polymerase chain reaction (RT-PCR).

Cells were separated according to the method of Jokhi [11], with minor modifications. Decidual tissue was incubated with 0.25% trypsin (Nakarai) in PBS containing 3% fetal calf serum (PBS/FCS) for 15 min at 37°C, and finely minced. Cells were resuspended in Rosewell Park Memorial Institute (RPMI) 1640 containing 10% FCS, 100 IU/ml penicillin, 100 µg/ml streptomycin, and 2.5 µg/ml amphotericin B (Nakarai) (RPMI 1640/FCS), then overlaid onto Ficoll-Paque (Pharmacia, Piscataway, NJ) and centrifuged at 600 x g for 20 min. The cells at the interface were removed, washed twice in PBS/FCS, and adjusted to a concentration of 1 x 10⁵ cells/ml in RPMI 1640/FCS. Immunocytochemistry confirmed that these decidual extracts were mostly stained with the antibodies for vimentin (in stromal cells) or CD45 (in leucocytes), but rarely with the antibodies for endoglin (in endothelial cells) and cytokeratin (in epithelial cells). After filtering through 40-µm nylon mesh, cells were incubated in 25-ml plastic flasks overnight at 37°C in 5% CO₂. The following day, nonadherent cells were discarded and the adherent cells were cultured in 10 ml of fresh RPMI 1640/FCS. The adherent cells consisted of approximately 90% stromal cells and 10% macrophages.

Semiquantitative RT-PCR

Samples were homogenized and total RNA was extracted by a TRIzol reagent (Gibco BRL, Gaithersburg, MD). Two ;gmg tRNA were converted to cDNA with 1 µg of oligo dT primers with a reverse transcription kit (Gibco BRL) in a final volume of 20 µl. One ;gml cDNA solution was amplified with 0.5 µM human IL-15-specific primers: upper 5'-GATTTACCGTGGCTTTGAGTAATGAG-3', lower 5'-GAATCAATTGCAATCAAGAAGTG-3' [23] in a final volume of 50 µl. Each cycle consisted of 60 sec at 94°C, 45 sec at 55°C, and 90 sec at 72°C. As an internal control, at the same time, human glyceraldehyde 3-phosphate dehydrogenase (G3PDH) mRNA was amplified with specific primers [24]. The number of cycles was determined when both IL-15 and G3PDH PCR products showed logarithmic proliferation. Ten ;gml of PCR products were subsequently electrophoresed on a 1.5% agarose gel (Pharmacia). After staining with ethidium bromide (Nakarai), products were verified as a band on the UV transilluminator (Funakoshi, Tokyo, Japan), and photographed. The band intensity was measured densitometrically using an image analyzer, NIH image 1.61 (NIH, Bethesda, MA), and analyzed statistically by Mann-Whitney U test.

Immunohistochemistry

Fixed samples were embedded in paraffin and cut into 4-µm sections. After being deparaffinized and rehydrated in a graded series of alcohol, sections were immersed in 3% hydrogen peroxidase to block endogenous peroxidase, and then in PBS containing 10% FCS to minimize nonspecific antibody binding. Sections were incubated with mouse anti-human IL-15 monoclonal antibody (MoAb; IgG₁, M112, Genzyme, Cambridge, MA) in a moist chamber. After washing in PBS, sections were incubated with peroxidase-labeled goat anti-mouse polyclonal antibody (Dako, Kyoto, Japan) for 30 min. After washing, sections were developed with diaminobenzidine (Dako) and counterstained with hematoxylin. Only the secondary antibody was used for the negative control.

Flow Cytometry

Decidual cells were separated by the standard Ficoll-Paque centrifugation method. Separated cells were incubated with anti-IL-15 MoAb for 15 min at room temperature and then washed twice with cold PBS/FCS, followed by incubation with fluorescein isothiocyanate (FITC)-conjugated goat anti-mouse IgG (Coulter, Fullerton, CA) for 15 min at room temperature. After addition of goat anti-mouse IgG polyclonal antibody, cells were incubated with mouse anti-human CD14 phycoerythrin (PE)-labeled MoAb (IgG₂a, RMO52, Coulter) or CD56 PE (IgG₁, NKH-1; Coulter) for 15 min at room temperature. The same subclass of labeled mouse IgG (Coulter) was used as a negative control. Cells were analyzed by a FACS-caliber and Cell Quest software (Becton-Dickinson, San Jose, CA). The quadrant marker was determined on a dotgram, which showed that as much as 95%–99.99% of IgG-stained cells were contained within the lower left quadrant.

Enzyme-Linked Immunosorbent Assay (ELISA)

Cells were cultured in the presence of 10^-6 M progesterone (Nakarai) dissolved in dimethylsulfoxide (Nakarai) as a vehicle, or dimethylsulfoxide as a control. After cells were cultured for 1–5 days, the supernatant was retrieved and frozen at -80°C until measured. Cell viability was measured by trypan blue dye-exclusion. Samples were used only when cell viability was greater than 90%. IL-15 concentration was quantitated by a commercial ELISA kit (R&D, Minneapolis, MN). The sensitivity of protein levels was 3.8 pg/ml.

RESULTS

Comparison of IL-15 mRNA Expression by Uterine Mucosa During Menstrual Cycle and First Trimester Pregnancy

Two isoforms of IL-15 mRNA were observed (Fig. 1a) as have been previously described [23, 25]. The 524-base pair (bp) band, corresponding to the long signal peptide (LSP) IL-15 mRNA, the stimulator of NK cells, was detected in all the samples examined, and its expression was significantly stronger in the secretory phase and first trimester decidua than in the proliferative phase (Fig. 1b). The 643-bp band, short signal peptide (SSP) IL-15, the function of which remains unknown, was also expressed more strongly in the secretory phase and first trimester decidua than it was in the proliferative phase (Fig. 1c). There were no significant differences between the secretory phase and first trimester in either isoform.

View larger version (33K): [in this window] [in a new window]   FIG. 1. RT-PCR analysis of IL-15 mRNA expression in human uterine mucosa. Four samples (a) selected from each phase are shown. Dotgrams display the LSP IL-15/G3PDH mRNA ratio (b) and SSP IL-15/G3PDH mRNA ratio (c) of each phase. P, proliferative phase; S, secretory phase; D, first trimester decidua; LSP, long signal peptide; SSP, short signal peptide

Localization of IL-15

During the proliferative phase, endometrial glandular epithelial cells were stained with the anti-IL-15 MoAb, whereas weakly stained cells were scattered in the stroma (Fig. 2a). During the secretory phase, immunoreactivity was elevated in endometrial stroma. This was prominent in perivascular cells around invading spiral arteries (Fig. 2c). During first trimester pregnancy, overall stromal cells and vascular endothelial cells were strongly stained (Fig. 2f).

View larger version (96K): [in this window] [in a new window]   FIG. 2. Localization of IL-15 in human uterine mucosa. Proliferative phase endometrium (a). Counterstaining was not performed to visualize partial staining of stromal cells. Negative control (b) for (a). Mid-secretory phase endometrium (c). Arrow points to perivascular stromal cells. Negative control (d) for (c). First trimester decidua (e,f). Arrows point to vascular endothelial cells. Negative control (g) for (e,f). Bars show 50 µm

Membrane-Bound IL-15 on the Surface of First Trimester Decidual Cells

Single color analysis showed a two-peak pattern of surface IL-15 distribution on decidual cells (Fig. 3a). Dual-color staining indicated that membrane-bound IL-15 was present on CD14++ macrophages and CD14- cells (Fig. 3b), but not on CD56++ NK cells (Fig. 3c).

View larger version (51K): [in this window] [in a new window]   FIG. 3. Membrane-bound IL-15 on the surface of first trimester decidual cells (data of a representative case). Histogram (a) showing two peaks of surface IL-15-positive cells (solid area). Open area indicates negative controls. Dual color analysis with anti-CD14 (b) and anti-CD56 (c)

IL-15 Secretion by Cultured Decidual Cells

On Day 2, detectable levels of soluble IL-15 were present in the supernatants of two of the progesterone-added (P+) groups, but not in any of the progesterone-free (P-) groups. On Day 3, soluble IL-15 was present in 5 of the P+ groups and 4 of the P- groups. On Day 4, soluble IL-15 was detected in all samples in both groups. The mean concentration of IL-15 was higher in the P+ groups than it was in the P- groups on each day.

DISCUSSION

Uterine NK cells are likely to contribute to embryo implantation and placental growth because of their cytokine production. It is reported that the proportion of CD16 to CD56++ NK cells was significantly decreased in the secretory phase endometrium in unexplained recurrent spontaneous abortion [26]. It is important to understand the mechanisms of proliferation and survival of these NK cells in human uterine mucosa. The aim of this study was to investigate the expression, localization, and variation of IL-15, a potent stimulator of uterine NK cells, in nonpregnant human endometrium and first trimester decidua.

In the current study, LSP IL-15 mRNA expression was higher during the secretory phase and first trimester decidua than it was in the proliferative phase. We also documented that IL-15 protein was localized in glandular epithelia and stroma of human endometrium. The immunoreactivity in stroma was elevated in mid- to late-secretory phase. IL-15 can stimulate proliferation and activation of entire lymphocyte subpopulation, and its proliferating effect on the CD56++ NK subset in peripheral blood is evident [18]. IL-15 is also known to have a key involvement in the differentiation of hematopoietic progenitor cells to NK cells [27, 28]. Uterine CD16–CD56++ NK cells express CD94/NKG-2A, an NK receptor, more brightly than peripheral blood NK cells do [29]. IL-15 is able to induce expression of CD94/NKG-2A on T cells and immature thymocytes [30, 31]. These observations suggest that IL-15 is a possible effector of uterine NK cells. Our observations suggest that IL-15 expression in human uterine mucosa corresponds to the variation of uterine NK cells and that its production is regulated by sex-steroid hormones, especially progesterone, as well as some other cytokines [32, 33].

Recently, IL-15 has been found on the surface of some macrophage cell lines and could stimulate the proliferation of T cells [34]. Other cytokines such as IL-1, IL-10, tumor necrosis factor (TNF)-, and TGF-ß have already been reported to exist in the membrane-bound form that is biologically active [35–38]. We also found the IL-15 molecule on the surface of decidual macrophages and CD14- cells. It is likely that this binding is not the result of the ligand-receptor complex because enzymatic digestion by trypsin did not significantly reduce its expression in comparison with nondigested samples (data not shown). Moreover, the membrane-bound form was not observed on decidual CD56++ NK cells. Judging from our cell separation technique, these CD14- cells with bright surface IL-15 were supposed to be decidual stromal cells. It is conceivable that cell-to-cell contact between endometrial stromal cells and NK cells is a prerequisite to proliferation and survival of uterine NK cells [39]. The strong expression of IL-15 on the surface of stromal cells may favor this hypothesis and we assume that IL-15 affects uterine NK cells mainly via a membrane-bound molecule.

We found soluble IL-15 in the supernatant of cultured decidual cells. Addition of progesterone stimulated its secretion. Many investigators have pointed to the difficulty of detecting IL-15 secretion by various cells and tissue culture systems, despite the bright expression of IL-15 mRNA. Although Bamford et al. [40–42] reported that IL-15 production was regulated at various points of translation, our results indicate the possibility that progesterone may be a crucial regulator of IL-15 synthesis.

In conclusion, IL-15 expression in human endometrium was higher in the secretory phase and first trimester decidua than in the proliferative phase and corresponded well to the fluctuation of NK cells in the endometrium. IL-15 production is thus likely to be controlled by hormones, especially progesterone.

View larger version (13K): [in this window] [in a new window]   FIG. 4. Secretion of IL-15 by cultured first trimester decidual cells (six samples) in the presence (a) or absence (b) of progesterone. The pair of a single sample was displayed using the same marker in each line chart

FOOTNOTES

First decision: 27 January 2000.

¹ Correspondence: Kotaro Kitaya, Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. FAX: 81 75 212 1265; kitaya{at}pop01.odn.ne.jp

Accepted: April 10, 2000.

Received: December 22, 1999.

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