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Medical Research Council Human Reproductive Sciences Unit (O.G., H.N.J.) and Department of Reproductive and Developmental Sciences (H.O.D.C.), University of Edinburgh, Centre for Reproductive Biology, Edinburgh EH3 9ET, United Kingdom; and Department of Pathology (J.M.B., A.K.), University of Cambridge, Cambridge CB2 1QP, United Kingdom
Address all correspondence and requests for reprints to: Dr. H. N. Jabbour, Medical Research Council Human Reproductive Sciences Unit, Center for Reproductive Biology, 37 Chalmers Street, Edinburgh EH3 9ET, United Kingdom. E-mail: . h.jabbour{at}hrsu.mrc.ac.uk
Abstract
Functional PRL receptors are expressed in the human endometrium during the secretory phase of the menstrual cycle in which PRL stimulates tyrosine phosphorylation of Janus kinase 2 and STAT (signal transducer and activator of transcription) 1 and 5. In this study, we investigated the effect of PRL on the MAPK/ERK pathway in the human endometrium. Human endometrial tissue was collected during the mid to late secretory phase of the menstrual cycle. Western blot analysis performed on proteins, extracted after up to 30 min culture with PRL, demonstrated rapid tyrosine and threonine phosphorylation of ERK 1 and 2 MAPKs. The phosphorylation of ERK, in response to PRL, was localized by immunohistochemistry to glandular epithelial cells and a subset of stromal cells. Using immunofluorescence histochemistry, PRL-induced phosphorylation of ERK in the stromal compartment was localized to the uterine-specific CD56+ natural killer (NK) cells. We have demonstrated that the PRL receptor is expressed in uterine CD56+ NK cells in situ by immunofluorescence and in purified decidual CD56+ NK cells by RT-PCR and Western blotting analysis. We have further demonstrated phosphorylation of ERK 1 and 2 in cultures of purified uterine CD56+ NK cells, in response to PRL. Our data demonstrate that PRL stimulates the ERK pathway in multiple cellular compartments of the human endometrium and identify uterine CD56+ NK cells as novel PRL target cells.
THE ENDOMETRIUM WAS one of the first extrapituitary sites that was described to synthesize and secrete PRL (1). In the absence of pregnancy, PRL synthesis is detected between the mid-secretory phase and menses, coinciding with the first signs of decidualization. If pregnancy occurs, decidual PRL synthesis increases after implantation, reaching a peak at 20–25 wk of pregnancy and declining toward term (2). Expression of PRL receptor (PRLR) is likewise up-regulated toward the secretory phase of the menstrual cycle within the human endometrium (3, 4) and is also maintained throughout pregnancy in the chorionic cytotrophoblast, placental trophoblast, and amniotic epithelium (5).
In the nonpregnant uterus, expression of PRL is confined to stromal cells of the endometrium (6). PRLR is also expressed in some stromal cells but is predominantly confined to the glandular epithelium of the endometrium (3, 4). PRL is thus envisaged to signal within the endometrium in an autocrine/paracrine fashion. The temporal expression of both PRL and PRLR suggests that PRL plays a role in preparing the endometrium for implantation as well as maintaining pregnancy (7).
Like other class I cytokines, PRL signals through the Jak (Janus kinase)/STAT (signal transducer and activator of transcription) pathway. In the human endometrium, PRL induces tyrosine phosphorylation of Jak 2 and STAT 1/5 within the glandular epithelial cells (3). To date, only one PRL-responsive gene has been identified within the human endometrium: interferon regulatory factor 1 (IRF-1) (8). Transcription of the IRF-1 gene is known to be directly stimulated by the Jak/STAT pathway (9), and expression of IRF-1 in the human endometrium is localized to the glandular epithelium as well as a subset of stromal cells (8).
In addition to the Jak/STAT pathway, many class I cytokines also stimulate the MAPK/ERK pathway. Signal transduction, leading to ERK activation from receptors, is achieved by the Shc/Grb2/Sos/Ras/Raf/MEK signaling cascade. The activated form of ERK (phosphorylated on residues threonine 202 and tyrosine 204) phosphorylates transcription factors (on serine and threonine residues) that regulate cellular differentiation and proliferation (for review, see Ref. 10).
In this study, we investigated PRL-induced ERK signaling in the human endometrium. We demonstrated that PRL stimulates the ERK pathway in multiple cellular compartments of the human endometrium. In addition to the glandular epithelium, the PRL-induced ERK activation was also localized to uterine CD56+ NK (natural killer) cells within the stromal compartment. Identification of uterine CD56+ NK cells as novel PRL target cells was further confirmed by analysis of PRLR expression and ERK phosphorylation in purified decidual CD56+ NK cells.
Materials and Methods
Endometrial tissue collection and culture
Normal human endometrial tissue (n = 9) was collected during the mid to late secretory phase of the menstrual cycle (22–30) by Pipelle suction curette (Laboratoires CCD, Paris, France) from fertile women with regular menstrual cycles (25–35 d of cycle) undergoing routine gynecological procedures. Approval from the Lothian Research Ethics Committee and written informed consent were obtained before tissue collection. To investigate the sites of expression of PRLRs in the endometrium, tissue (n = 4) was dissected and fixed in neutral buffered formaldehyde for immunofluorescence analysis (PRLR and CD56 colocalization) or snap-frozen for Western blot analysis (PRLR). To investigate the effect of PRL on ERK phosphorylation, endometrial tissue (n = 5) was incubated overnight in serum-free RPMI 1640 medium (Sigma, Dorset, UK) containing 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin and treated with 100 ng/ml human PRL (hPRL-SIAFP-B2, donated by NIDDK, NIH) for 0, 5, 10, 20, and 30 min. The tissue was stored at -70 C before analysis by Western blotting. To investigate the sites of ERK phosphorylation in response to PRL, endometrial tissue (n = 4) was incubated overnight as described above and subsequently treated with or without 100 ng/ml human PRL for 30 min. Where indicated, tissue was preincubated with 50 µM MAPK kinase (MEK) inhibitor PD98059 (Calbiochem-Novabiochem Ltd., Nottingham, UK) for 3 h before addition of PRL.
Isolation and culture of decidual CD56+ NK cells
Pooled fragments of decidua parietalis from first-trimester pregnancy (n = 2) were combined from two and three patients, as described before (11). Decidual tissue was digested with 2 mg/ml collagenase type V (Sigma) at 37 C for 1 h (or 0.6 mg/ml at room temperature overnight) on a rolling machine; this was followed by density gradient centrifugation on Lymphoprep. The CD56+ cells were then isolated using immunomagnetic separation; the cells were labeled with CD56 Macsbeads (Miltenyi Biotec, Bergisch Gladbach, Germany) and separated from unlabeled cells via a column placed in a strong magnetic field. Then the cells were cultured overnight in 1% human AB serum in RPMI 1640 medium (Sigma) containing 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin; treated with 100 ng/ml PRL for 0, 10, 20, or 30 min; and stored at -70 C before Western blot analysis. Flow cytometric analysis of decidual lymphocytes prepared in this way revealed that less than 2% were CD3+ and between 95 and 99% were CD56+ (11).
Cell culture and transfection of cell lines
Human embryonic kidney 293 fibroblasts and human breast T47D cells were routinely grown in complete medium (DMEM nutrient F-12 containing 100 U/ml penicillin, 100 µg/ml streptomycin, and 10% FCS). For transfection, 2 x 105 293 fibroblast cells were seeded in Petri dishes of 40 mm diameter and transfected with 2 µg PRLR cDNA in pcDNA3 (provided by Prof. P. Kelly, INSERM, Unite 344, Paris, France) using pfx5, according to the manufacturer’s instructions (Invitrogen Corporation, Carlsbad, CA). Cells were then incubated for another 24 h in complete medium before lysis.
Immunohistochemistry/immunofluorescence
Tissue was fixed in neutral buffered formaldehyde, prepared as paraffin wax-embedded sections, and cut and mounted on slides. Slides were dried overnight at 50 C and dewaxed in xylene. Tissue was rehydrated in graded ethanol and washed in water followed by PBS. Sections were heated in 10 mM sodium citrate for 5 min in a pressure cooker, incubated with 20% normal porcine serum in PBS for 1 h, and washed in PBS twice for 5 min each time. Then the sections were incubated with antiphospho ERK 1/2 antibody (T202/Y204, Cell Signaling, New England Biolabs, Inc., Beverly, MA) and diluted 100-fold in 20% normal porcine serum in PBS for 1 h. Sections were washed twice in PBS again for 5 min, incubated with biotinylated porcine antirabbit IgG (DAKO Corp., Glostrup, Denmark), and diluted 500-fold in 20% normal porcine serum in PBS. Sections were washed as before, incubated with an avidin-biotin peroxidase detection system (DAKO Corp.), and incubated for 2–10 min with diaminobenzidine solution (Sigma) for color development. Sections were counterstained with hematoxylin, dehydrated, cleared, and mounted in xylene. For immunofluorescence, sections were prepared and pressure-cooked as described above and incubated with 20% porcine and goat serum in PBS. Sections were then incubated for 1 h with antibodies against phosphorylated ERK (Cell Signaling, New England Biolabs, Inc.), CD56 (Zymed Laboratories, Inc., San Francisco, CA), or PRLR (provided by Prof. Charles Clevenger, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA), each diluted 50-fold in 20% porcine/goat serum in PBS. Sections were washed twice in PBS for 5 min and incubated with tetramethylrhodamine isothiocyanate (TRITC)-conjugated porcine antirabbit antibody (DAKO Corp.) and fluorescein isothiocyanate (FITC)-conjugated goat antimouse antibody (Sigma), diluted 30-fold in 20% porcine/goat serum in PBS. Sections were again washed in PBS twice for 5 min and mounted directly in cytofluor. Fluorescence was detected by confocal microscopy.
Western blotting
Tissue was homogenized and lysed in 150 mM NaCl, 10 mM Tris (pH 7.4), 1 mM EDTA, 10% glycerol, 0.6% Nonidet P-40, 10 µg/ml aprotonin, 1 mM phenylmethylsulphonyl fluoride, and 1 mM sodium orthovanadate. Cytoplasmic extracts were prepared by centrifugation for 2 min at 14,000 rpm. A total of 50 µg protein was subjected to SDS-PAGE and then transferred to polyvinylidene fluoride membrane (Millipore Corp., Bedford, MA). Membranes were incubated with antibodies against ERK 1/2 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), phosphorylated ERK 1/2 (T202/Y204), and PRLR each diluted 1000-fold in 2% dried skimmed milk/TBST [20 mM Tris-HCl (pH 7.4), 500 mM NaCl, 0.1% Tween 20]. Membranes were washed briefly in TBST and incubated with secondary antibodies conjugated to horseradish peroxidase (Amersham Pharmacia Biotech plc, Buckinghamshire, UK) in 2% milk/TBST. Membranes were again washed in TBST, and proteins were detected using the ECL+ detection kit (Amersham Pharmacia Biotech plc).
RT-PCR
RNA was prepared from pelleted cells or tissue by lysis in Tri Reagent (Sigma). RT reactions were conducted in a volume of 50 µl consisting of 2 µg total RNA, 10 ng oligo-dT (Invitrogen Corporation), 0.1 M dithiothreitol, 10 mM deoxynucleotide triphosphates, and Superscript reverse transcriptase (Invitrogen Corporation). PCR was performed in 25 µl reactions, with 2 µl of the RT reaction, using reagents provided by Hybaid (Middlesex, UK). PCR samples were heated at 94 C for 2 min, followed by 30 cycles of 94 C for 30 sec, 55 C for 30 sec, and 72 C for 30 sec, and an extension time of 5 min at 72 C. Primers (sense, 5'-GCAGATGGAGGACTTCCTACCAATTA-3'; and antisense, 5'-GCAGGTCACCATGCTATAGCCCTT-3') were used to amplify 650 bp of the extracellular domain of PRLR. PCR fragments were visualized by ethidium bromide staining on agarose gels.
Results
Effect of PRL on the MEK/ERK pathway in human endometrium
To investigate the effect of PRL on the ERK/MAPK pathway in human endometrium, tissue was treated with 100 ng/ml PRL, and lysates were analyzed by Western blotting using antibodies against phosphorylated (T202/Y204) and native ERK (both ERK antibodies react with the ERK isoforms ERK 1 and ERK 2, p44 and p42, respectively). Phosphorylation of ERK 1 and 2 was observed after only 5 min treatment with PRL, with increased phosphorylation at 20 and 30 min (Fig. 1A
). To demonstrate whether this PRL-induced ERK signal was dependent on the ERK kinase, MEK, the experiment was repeated in the presence and absence of 50 mM inhibitor PD98059 (Fig. 1B). The stimulation of ERK, observed after 15 and 30 min treatment with PRL, was inhibited in the presence of PD98059, indicative of the requirement of MEK activation for ERK phosphorylation.
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To investigate the sites of PRL-induced ERK phosphorylation within the human endometrium, tissue was treated with PRL for 30 min in the presence or absence of 50 µM PD98059 and analyzed immunohistochemically using antibody against phosphorylated ERK (Fig. 2). In the presence of PRL, phosphorylated ERK was localized to glandular epithelium (Fig. 2B). As expected, the presence of PD98059 reduced this staining, indicating that the observed phosphorylation of ERK was dependent on MEK (Fig. 2C). However, in addition to the glands, phosphorylated ERK was also identified in a subset of stromal cells (Fig. 2E). To further investigate whether the PRL-induced ERK phosphorylation within the stroma is located to immune cells, phosphorylation of ERK in response to PRL was examined in the CD56+ NK cells, the predominant leukocyte population in the human secretory endometrium (12). Endometrial tissue was treated with 100 ng/ml PRL and examined by double immunofluorescence using antibodies against both CD56 and phosphorylated ERK (Fig. 3). A subset of stromal cells, positive for CD56, were also positive for phosphorylated ERK (Fig. 3C), indicating that PRL induced ERK phosphorylation in the uterine CD56+ NK population. However, some stromal cells that were positive for phosphorylated ERK were negative for CD56, suggesting that PRL may also induce ERK phosphorylation in a stromal cell type other than CD56+ NK cells.
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To examine PRLR expression in CD56+ cells of the human endometrium, endometrial tissue was examined by double immunofluorescence using antibodies against both CD56 and PRLR (Fig. 4). The PRLR-positive cells were localized most obviously to the glandular epithelium; however, a subset of positive cells were also present in the stromal compartment (Fig. 4A). The CD56 positive cells within the stroma were also positive for PRLR, indicating that PRLR is expressed in the CD56+ NK cell population of the endometrium (Fig. 4C). However, as for the localization of phosphorylated ERK observed in Fig. 3
, some stromal cells that were positive for PRLR were negative for CD56. This further indicates the presence of PRL-responsive cell types in addition to uterine CD56+ NK cells within the stromal compartment.
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). PCR fragments of the expected size were detected from RNA extracted from secretory phase endometrium and T47D cells but absent from RNA extracted from 293 fibroblasts. PCR fragments were also generated from RNA extracted from purified uterine CD56+ NK cells, indicating that the decidual CD56+ NK cells express PRLR mRNA. To confirm PRLR expression at the protein level in these purified uterine CD56+ NK cells, lysates were analyzed by Western blotting using an antibody generated against the extracellular domain of PRLR (Fig. 5B). Two bands of approximately 85 and 90 kDa were detected in lysates prepared from secretory phase endometrium and CD56+ cells (5). In T47D cells, a predominant band of approximately 90 kDa was detected. To confirm that these bands correspond to the PRLR, 293 fibroblasts were transiently transfected with PRLR and compared in parallel by Western blotting using the same anti-PRLR antisera. Immunoreactive proteins of 85 kDa and, to a lesser extent, 90 kDa were observed only in 293 fibroblast cells after transfection with the PRLR cDNA. The presence of multiple immunoreactive bands likely reflects the effect of posttranslational modifications such as glycosylation. (The predicted size of PRLR, based on amino acid sequence, is 69.5 kDa.)
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To confirm that PRL induces phosphorylation of ERK in the CD56+ NK cell population, we investigated whether PRL could also induce ERK phosphorylation in purified, cultured CD56+ NK cells. Cultures of purified decidual CD56+ NK cells were treated with 100 ng/ml PRL for up to 30 min and analyzed by Western blotting using antibodies against phosphorylated and native ERK (Fig. 1). Increasing phosphorylation of ERK 2 and particularly ERK 1 was observed after treatment with PRL for 10 and 20 min; however, phosphorylation was reduced at 30 min (Fig. 6).
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In this study, we have demonstrated that PRL induces the MEK/ERK/MAPK pathway within the secretory phase of the human endometrium. The PRL-induced ERK phosphorylation was localized to glandular epithelium and a subset of stromal cells. Further investigation to identify the PRL-responsive cells within the stroma led us to identify novel PRL target cells within the human endometrium, i.e. the uterine CD56+ NK cells. Expression of PRLR in uterine CD56+ NK cells was further confirmed in purified decidual CD56+ NK cells by RT-PCR and Western blotting, and in situ by immunofluorescence analysis. Lastly, we confirmed that PRL induces ERK phosphorylation in cultures of purified decidual CD56+ NK cells by Western blotting analysis. The data therefore demonstrate that PRL induces the ERK pathway not only in glandular epithelial cells but also in uterine-specific CD56+ NK cells. Our results are consistent with previous studies that demonstrate PRLR expression in glandular tissue and a subset of stromal cells of the endometrium (3, 4). Previous data from our laboratory have also demonstrated that PRL induces phosphorylation of Jak 2 and STAT 1/5 in the glandular epithelial cells (3). Taken together, the data indicate that PRL activates divergent signaling pathways in the glandular epithelial cells of the human endometrium, i.e. the Jak/STAT and ERK pathways.
ERK activation by PRL has been reported in other model systems, such as human liver (14), rodent Nb2 T-cell line (15), human mammary T47D cells (16), and human breast carcinoma (17). In the Nb2 T cell line, ERK activation is necessary for the mitogenic effect of PRL on these cells (18). The glandular epithelial cells of the mid to late secretory phase, however, are no longer proliferating at this stage of the menstrual cycle and exhibit expression of differentiation-specific genes involved in secretory function. PRL, therefore, likely plays a role in differentiation of the glandular epithelium via both Jak/STAT and ERK signaling pathways. The involvement of both signaling pathways acting together to influence differentiation is documented for other cell types such as neuronal (19), blood (20), and fat (21) cells. In some cases, STAT proteins themselves have been identified as the substrate for ERK (22, 23), indicating that the ERK kinase may act directly to modulate STAT function.
An increasing body of evidence indicates that PRL acts as a general immunoregulatory agent throughout the body (24, 25). For example, hypophysectomy or bromocriptine treatment in mice suppresses the growth of the thymus (26), T cell proliferation, and interferon 
production (27). Previous in vitro studies demonstrate that PRL is associated with lymphoid cell differentiation (for review, see Ref. 24), and together with other factors such as IL-2, stimulates proliferation of B and T cells (27, 28, 29, 30) by transcriptional activation of growth-related genes (31, 32). PRL also serves as a mitogen for peripheral NK cells and macrophages (27, 33). The expression of PRLR in uterine CD56+ NK cells is perhaps not surprising because the majority of leukocytes are documented to express PRLR (34, 35, 36, 37). The observation that some stromal cells were positive for phosphorylated ERK and PRLR but negative for CD56 (Figs. 3 and 4) is suggestive that other PRL-responsive cell type(s) exist within the stroma, possibly macrophages or T cells. However, although a role for PRL as a stimulator of either leukocyte proliferation or differentiation in the endometrium has been postulated (4, 7), there is so far no direct evidence of such a role for PRL in the regulation of leukocytes in the endometrium.
The transformation of endometrium to decidua is essential for successful implantation. One characteristic feature of decidua is the presence of the distinctive population of uterine mucosal CD56 bright NK cells. These are always associated with the process of decidualization and account for about 70% of bone marrow-derived cells in the endometrium (12). In humans, CD56+ NK cells become prominent in nonpregnant secretory phase endometrium as part of the predecidualization process (38). It is not clear what role CD56+ NK cells have, although their concentration around invading trophoblast cells (39) and blood vessels (40) suggests that they are important for implantation and control of blood supply for both the fetoplacental unit and onset of menstruation. A role for CD56+ NK cells in angiogenesis within the endometrium is further suggested by the presence of angiogenic factors expressed in this cell population (41). The abundance of NK cells in the secretory phase endometrium is thought to be due to a selective influx of leukocytes from the periphery, but more significantly to their ability to proliferate in situ (42, 43). In the event of pregnancy, NK cells persist in the decidua; however, their proliferation is less pronounced. The coincidence of increased PRL secretion from the stroma and the accumulation of CD56+ NK cells within mid to late secretory phase endometrium is consistent with a possible role for PRL to promote CD56+ NK cell growth. In addition to cell growth, PRL may also play a role in the maturation of uterine CD56+ NK cells. This maturation process may be dependent on the transcription factor IRF-1, which is important for peripheral NK cell maturation (44). This is supported by previous studies from our laboratory that demonstrate IRF-1 expression is localized to a subset of stromal cells and is up-regulated by PRL in the endometrium (8).
How signaling is achieved between the PRLR and ERK pathway in the human endometrium is unclear. In the presence of PRL, the PRLR-associated kinase Jak 2 is required for the interaction between Shc and Grb2 in Nb2 cells (45) and is further shown to interact with Shc in mammary cell lines (16). Similarly, Yamauchi et al. (14) demonstrated that Jak 2 directly phosphorylates the epidermal growth factor receptor in the liver, creating docking sites for the SH2 domains of signaling factors such as Shc and Grb2. However, another PRLR-associated kinase, Fyn (46), may also play a role in PRL-induced ERK activation. For fibroblast and T cell lines, Fyn induces the ERK pathway by phosphorylation of the guanine-nucleotide exchange factor SOS (47, 48). Both Jak 2 and Fyn are phosphorylated in the human endometrium in response to PRL (3, 49) and may thus be required for ERK activation within the human endometrium.
In conclusion, we have demonstrated that, in addition to the glandular epithelial cells, CD56+ NK cells are also PRL-responsive cells of the human endometrium. We have also shown that PRL stimulates the ERK signaling pathway within both of these cellular compartments. Further research is required to determine the significance of this observation; however, we postulate that the PRL-induced ERK pathway serves a function in differentiation of the glandular epithelium and may influence the growth of uterine CD56+ NK cells during the peri-implantation period.
Acknowledgments
We are grateful to Prof. Charles Clevenger for providing us with antibody against PRLR and Prof. Paul Kelly for providing us with PRLR cDNA. We also thank Mike Millar and Sheila McPherson for technical assistance.
Footnotes
This work was supported by WellBeing (reference no. 2256).
Abbreviations: IRF-1, Interferon regulatory factor 1; Jak, Janus kinase; MEK, MAPK kinase; NK, natural killer; PRLR, PRL receptor; STAT, signal transducer and activator of transcription; TRITC, tetramethylrhodamine isothiocyanate.
Received November 13, 2001.
Accepted February 11, 2002.
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