Molecular Human Reproduction, Vol. 6, No. 10, 907-914,
October 2000
© 2000 European Society of Human Reproduction and Embryology
Uterine physiology |
Expression of interleukin-11 during the human menstrual cycle: coincidence with stromal cell decidualization and relationship to leukaemia inhibitory factor and prolactin
1 Prince Henry's Institute of Medical Research, 3168 Clayton, Victoria, and 2 The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Royal Melbourne Hospital, Parkville, 3050 Victoria, Australia
Abstract
Interleukin-11 (IL-11) is crucial in the decidualization response of the uterine stroma to the implanting blastocyst in the mouse. This study examined the localization and expression of IL-11 in human endometrium throughout the menstrual cycle and of prolactin and leukaemia inhibitory factor (LIF) in secretory phase endometrium. The mRNA expression of IL-11 receptor 
and the signalling component, gp130, in endometrial tissue were also determined. Immunoreactive IL-11 was highest in the secretory phase and present in decidualized stromal cells, glandular epithelial cells, endothelial and smooth muscle cells, and the mRNA expression was verified by in-situ hybridization. Decidual cells showed the most intense staining. IL-11 receptor and gp130 mRNA were detected throughout the cycle with minimal variation. Expression of IL-11 mRNA and protein preceded that of prolactin. While immunoreactive prolactin was found in stromal, decidual and glandular epithelial cells, prolactin mRNA was confined to decidual cells. In contrast, endometrial LIF expression preceded IL-11 but was largely confined to the glandular epithelium. The sequence of appearance of LIF, IL-11 and prolactin suggests a synchronized role for each in the differentiation of the endometrium. The cyclical changes and cell type specific expression of IL-11 suggests a potential role in the decidualization of stromal cells.
decidualization/endometrium/interleukin-11/LIF/prolactin
Introduction
Interleukin-11 is a cytokine with pleiotropic activities on a range of cell types (Du and Williams, 1997
). Similar to other members of the interleukin-6 (IL-6)-like family of cytokines, e.g. leukaemia inhibitory factor (LIF), IL-11 signals via a receptor complex composed of a specific binding chain, the IL-11 receptor (IL-11R) and the signalling component, gp130 (Hilton et al., 1994). IL-11 was initially described as a growth factor, acting at multiple stages during haematopoiesis. It synergizes with other factors to stimulate progenitor cells and also stimulates cells of thrombopoietic, erythroid and lymphoid lineages (Du and Williams, 1994, 1997). IL-11 also has an anti-inflammatory activity (Sands et al., 1999), while actions in bone remodelling (Maier et al., 1993), neuronal differentiation (Mehler et al., 1993) and female fertility in the mouse (Robb et al., 1998) have also been described.
The endometrium is a rich source of cytokines that are important in embryo implantation (Tabibzadeh and Babaknia, 1995; Sanchez-Cuenca et al., 1999). A great deal of information regarding the essential roles of cytokines in fertility has been generated from studies examining mice with alterations in genes encoding cytokines and their receptors. Those with effects on fertility via endometrial dysfunction include macrophage-colony stimulating factor (M-CSF) (Pollard et al., 1991) and LIF (Stewart et al., 1992). Another group (Robb et al., 1998), demonstrated that female mice with a null mutation of the IL-11R chain were infertile due to a defective post-implantation decidual response of the uterine stroma to the implanting blastocyst. In another study, genetically targeted mice with a hypomorphic IL-11R allele had a retarded decidualization response and the decidua degenerated prior to the formation of a chorio–allantoic placenta (Bilinski et al., 1998).
Although IL-11 is crucial in the decidual response to the implanting blastocyst and, therefore, in fertility in the female mouse, there are no studies examining its role in fertility in the primate. In the human female, the remarkable event of decidualization of the stromal cells occurs spontaneously in the late secretory phase of the menstrual cycle, not post-implantation (as in the mouse), and is not dependent on the presence of a blastocyst. It involves morphological changes indicative of a mesenchymal–epithelial transition and biochemical changes reflected by the expression of new products in a highly coordinated manner (Tabibzadeh and Babaknia, 1995). Indeed, expression of prolactin (PRL) is commonly used as a marker of decidual transformation (Braverman et al., 1984). If implantation occurs, stromal cell decidualization continues and decidual cells are maintained throughout pregnancy. Therefore factors involved in decidualization are important both for implantation and for subsequent placentation.
This study was designed as a first step in elucidating the role of IL-11 in human fertility. We examined the cellular localization and expression pattern of IL-11 in the human endometrium throughout the menstrual cycle using immunohistochemistry. The expression of endometrial IL-11R and gp130 mRNA was also determined using reverse transcription–polymerase chain reaction (RT–PCR). The sequential appearance of IL-11, LIF and PRL mRNA in secretory phase endometrial tissue was examined by in-situ hybridization.
Materials and methods
Tissues
Endometrial tissue was obtained by curettage from women who gave informed consent and had regular menstrual cycles with no apparent endometrial dysfunction. Approval was given by the Human Ethics Committee at Monash Medical Centre, Melbourne, Australia. The women were either of proven fertility and were scheduled for tubal ligation or were undergoing testing for patency of the Fallopian tubes. The women were not taking any steroid hormones. Tissue samples were formalin fixed for 16–20 h, washed in Tris-buffered saline (TBS) and processed to paraffin wax blocks. Sections were cut at 5 µm, hydrated, and stained with haematoxylin for histological dating of the menstrual cycle by an experienced gynaecological pathologist according to a previously described method (Noyes et al., 1950). Specimens were classified according to an idealized 28 day reproductive cycle and then grouped into menstrual phase (ME; days 1–4), early (EP; days 5–8) and late proliferative (LP; days 9–13) phases, early (ES; days 14–18), mid- (MS; days 19–23) and late secretory (LS; days 24–28) phases.
Immunohistochemistry
Immunolocalization of IL-11 in the human endometrium was performed using a commercially available anti-huIL-11 monoclonal antibody (MAB618; R&D Systems Inc, Minneapolis, MN, USA). Human term placental tissue was used as a positive control and one section from the same tissue block was included in every staining run for quality control. A negative control was included as a second section on each slide where instead of the primary antibody, normal mouse immunoglobulin G (IgG) at the same protein concentration as the primary antibody was applied. As an additional control, preadsorption was performed by incubating the IL-11 antibody with recombinant human IL-11 (Eschrichia coli) at a 1:90 molar ratio for 7 days at 4°C prior to immunohistochemistry.
Immunohistochemistry was performed on rehydrated 5 µm tissue sections. All procedures were carried out at room temperature except for the incubation with the primary antibody that was performed at 4°C. The sections were treated with 3% hydrogen peroxide in methanol for 10 min and then with 10% normal horse serum (NHS) and 10% fetal calf serum (FCS) in TBS (pH 7.6) for 30 min followed by incubation with anti-huIL-11 diluted in 10% FCS/TBS at 4°C for 16 h. The tissues were then washed and incubated in biotinylated horse anti-mouse IgG (Vector Laboratories Inc., Burlingame, CA, USA, 1:200) for 1 h followed by streptavidin–biotin–peroxidase complex ABC Elite (Vector, Burlingame, CA, USA) according to the manufacturer's instructions. Peroxidase activity was visualized following the application of diaminobenzidine tetrahydrochloride (DAB) substrate (Zymed Laboratories Inc, South San Francisco, CA, USA). Sections were counterstained with Harris haematoxylin, dehydrated and mounted. Microscopy was performed using an Olympus BH2 microscope and photographed using an Olympus camera with ND and LBD2N filters. A total of 32 endometrial tissues from across the menstrual cycle were examined. Immunostaining intensity within individual cellular compartments was scored by two observers. The scoring ranged from 0 (no staining) to 4 (maximal staining) in relation to the positive and negative controls and takes into account both the staining intensity and proportion of any one cell type stained.
Immunohistochemistry was also performed for LIF in mid- and late secretory phase tissue using a polyclonal antiserum raised in rabbit against human LIF protein (AMRAD Pharmacia Biotech, Boronia, Victoria, Australia) as previously described with minor modifications (Vogiagis et al., 1996). Briefly, the primary antibody (1:2000) was incubated for 12 h at room temperature. After washing, slides were incubated in biotinylated swine anti-rabbit IgG (Dako, Glostrup, Denmark; 1:200) for 60 min followed by the application of streptavidin–biotin–peroxidase complex (Vector Laboratories Inc, Burlingame, CA, USA) according to the manufacturer's instructions.
Immunohistochemistry was also performed for PRL in mid- and late secretory phase tissues and this followed a similar protocol to that of LIF except that a rabbit polyclonal against human pituitary PRL (National Institutes of Health, Bethesda, MD, USA) was used as primary antibody (1:200) and it was incubated for 60 min at room temperature.
In-situ hybridization
The full length human IL-11 cDNA was used as a riboprobe. For the PRL and LIF riboprobes, 694 bp (PRL) and 569 bp (LIF) fragments of the cDNAs were amplified by PCR and cloned into Bluescript SK. Antisense and sense digoxigenin (dig)-labelled RNA probes against IL-11, LIF and PRL were generated using a DIG RNA labelling kit (Boehringer Mannheim Biochemica, Mannheim, Germany). In-situ hybridization was performed as follows. Sections (5 µm) of formalin-fixed, paraffin-embedded tissue were de-paraffinized, rehydrated and digested with proteinase K (10µg/ml in 100 mmol/l Tris–HCl, 50 mmol/l EDTA, pH 8.0) for 30 min at 37°C and post-fixed in 4% paraformaldehyde at 4°C for 10 min. The tissue sections were pre-hybridized for 10 min at 48°C in 4x SSC (1x SSC: 150 mmol/l NaCl, 15 mmol/l tri-sodium citrate, pH 7.0)/50% formamide, followed by overnight hybridization at 48°C in 50 µl hybridization buffer consisting of 1x salt solution [0.3 mol/l NaCl, 0.1 mol/l Na2HPO4, 50 mmol/l EDTA, 1% Ficoll 400, 0.1 mol/l Tris–HCl, pH 7.5. 0.2% polyvinyl pyrolidone, 0.2% bovine serum albumin and 0.005% diethylpyrocarbonate (DEPC)], 10–20 ng of dig-labelled RNA probe, 50% formamide, 10% dextran sulphate, 1x Denhardt's solution, 10 mmol/l dithiothreitol (DTT), 1 mg/ml yeast-RNA and 0.1 mg/ml herring spermatozoa. The sections were then washed with 50% formamide/2x SSC followed by 50% formamide/1x SSC both for 15 min at 48°C. This was followed by treatment with RNase A (20 µg/ml) for 30 min at 37°C. The sections were sequentially washed twice each with 1x SSC followed by 0.1x SSC for 30 min at 48°C. Following washing with buffer 1 (0.1 mol/l Tris, 150 mmol/l NaCl, pH 7.5) for 10 min at room temperature, blocking solution was applied containing 0.1% Triton X-100, 15% normal sheep's serum in buffer 1 for 1 h. Anti-dig-alkaline phosphatase (1:300) in blocking solution was then applied overnight at 4°C after which the colour reaction was developed with 5-bromo-4-chloro-3-indoxyl phosphate/nitro-blue tetrazolium chloride (BCIP/NBT) solution (Dako Corporation, Carpinteria, CA, USA) for 2 h in the dark at room temperature.
Term placental tissue served as a positive control for IL-11 and first trimester decidua was used for PRL. Sections hybridized with the corresponding sense probes served as negative controls. Hybridization specificity was verified by abolishment of signal following pretreatment with RNase prior to hybridization with antisense riboprobe.
RT–PCR
Total RNA was prepared from a portion of endometrial biopsy samples using Trizol (Life Technologies Inc, Rockville, MD, USA). Samples were treated with DNase I (Boehringer Mannheim, Mannheim, Germany) and oligo(dT)-primed first strand cDNA synthesis from 1 µg RNA was performed using avian myeloblastosis reverse transcriptase (Boehringer Mannheim). Aliquots (1 µl) of five-fold serial dilutions of each sample were amplified by PCR with primers for glyceraldehyde phosphate dehydrogenase (GAPDH) using 20 cycles of 94°C/30 s, 60°C/30 s, 72°C/1 min, in a reaction mixture containing 1x PCR buffer (Boehringer Mannheim) 60 µmol/l of each dNTP, 1.25 IU Taq polymerase (Boehringer Mannheim) preincubated with TaqStart antibody (Clontech, San Diego, CA, USA) at a ratio of 1:1 and 0.5 µmol/l of each specific primer. The product was electrophoresed on a 2% agarose gel, transferred to GeneScreen Plus (Dupont, Wilminton, DE, USA) and the filter hybridized with a [32P]-end labelled internal oligonucleotide. The primer pairs were as follows:
IL-11R:5'-CAGGGCCTGCGGGTAGAGTCAGTA-3'
5'-CTCCTTTGGTATGGTCCCAGTGCT-3'
gp130:5'-TAAAGGCATACCTTAAACAAGC-3'
5'-GTGAATTCTGGACCATCCTTCC-3'
GAPDH:5'-ACCACAGTCCATGCCATCAC-3'
5'-TCCACCACCCTGTTGCTGTA-3'
All primers were selected to cross introns. Reaction conditions were as above, except that the annealing temperatures and cycle numbers were: IL-11R: 65°C, 32 cycles; gp130: 62°C, 32 cycles.
Results
Immunoreactive IL-11 was observed in all human endometrial tissues except those of the early proliferative phase. The relative staining intensities in the individual cellular compartments and at different stages of the cycle are detailed in Figure 1 and representative photomicrographs can be seen in Figure 2. There were distinct differences in staining patterns of the various cell types between the menstrual, proliferative and secretory phases. Very little staining was seen in the menstrual, proliferative (Figure 2A) and early secretory phases. In the menstrual phase, very pale staining was seen in the glandular epithelial cells and stromal cells (Figure 1). In the early secretory phase, light staining was seen in the luminal and glandular epithelial cells (Figures 1 and 2B). However, in the mid-secretory phase staining intensity of glandular epithelial cells increased to a moderate level to be the most intensely stained cell type in that phase (Figures 1 and 2C) and increased further in the late secretory phase (Figures 1 and 2D). Where present, the luminal epithelial cells stained positively in the secretory phase and the staining intensity was at its highest in the late secretory phase (Figure 1). IL-11 immunoreactivity was also found in the vasculature only in the secretory phase endometrial biopsies. Both the vascular smooth muscle cells and the endothelial cells were highly stained in the late secretory phase (Figures 1 and 2D). By contrast, immunostaining in the stromal fibroblasts varied little in intensity in the secretory phase of the cycle (Figure 1). Although the extent of decidualization of the stromal cells varied between tissues, the decidualized stromal cells were always present in the late secretory phase. The decidual cells were scored separately and showed the strongest immunostaining intensity of all the cell types in the late secretory phase (Figures 1 and 2D inset).
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Immunoreactive LIF was detected in secretory phase endometrial biopsies predominantly in the glandular and luminal epithelium (Figure 2G–I
). The early and mid-secretory phase tissues were the most highly stained while the late secretory phase tissue stained to a lesser intensity. Slight staining in the stroma was also seen in the late secretory phase.
In the tissue sections from the same blocks that had been stained for IL-11 and LIF, positive PRL immunoreactivity was evident only in mid- and late secretory phase tissue (Figure 2K–M). The decidual cell was the most intensely stained cell type in the tissue. However, lower staining intensity was also seen in the glandular epithelial cells and stromal cells.
Tissue sections of secretory phase endometrial tissue were examined by in-situ hybridization for LIF, IL-11 and PRL mRNA. There was considerable variability between expression patterns of the three mRNA species, both in the day of the cycle when expression was first observed, and in the cellular location. Sense control probes for all three mRNA gave similar background staining to that shown in Figure 3D, H and M.
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In-situ hybridization of mRNA for IL-11 confirmed the cellular location for synthesis of this cytokine in the endometrium as demonstrated by immunohistochemistry. Very little hybridization was seen in the glands, stroma or vasculature on days 19 (Figure 3A
) and 21 (Figure 3B). In the late secretory phase, IL-11 mRNA was detected in the decidualized stromal cells in some but not all, endothelial and vascular smooth muscle cells and glandular epithelial cells (Figure 3C). IL-11 mRNA was also present in syncytiotrophoblast in term placenta (Figure 3I).
In contrast, LIF mRNA was detected in the glandular epithelial cells by the mid-secretory phase (day 19, Figure 3E), and this was even more intense by day 21 (Figure 3F). However, by day 28, LIF mRNA had disappeared (Figure 3G). Neither stromal cells, nor cells associated with the vasculature were consistently positive for mRNA encoding LIF, verifying a previous report (Cullinan et al., 1996).
PRL mRNA was not detectable until the late secretory phase when it was highly expressed in the decidualized stromal cells (Figure 3L). It was also highly expressed in first trimester decidual tissue (Figure 3J).
Thus, it is apparent that the mRNA encoding these three proteins, appears in the human endometrium sequentially, with LIF appearing first in the glands, followed by IL-11 in the glands and in the decidualizing stromal cells while PRL does not appear until decidualization is well advanced in the late secretory phase of the cycle when it is detected only in the decidualized stromal cells.
The expression of genes encoding the IL-11R and gp130, the two components of the IL-11 signalling complex, was examined by RT–PCR in RNA prepared from endometrial biopsies from different stages of the menstrual cycle. Expression was detected throughout the menstrual cycle and in samples from first trimester and term placenta (Figure 4). Although the method used does not allow reliable quantification, there appeared to be no marked variation in the expression of IL-11R and gp130 mRNA across the menstrual cycle.
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Discussion
This is the first description of the expression and localization of IL-11 in the human endometrium across the menstrual cycle. All the major cell types in the endometrium express IL-11 with cyclical variation. IL-11 mRNA and protein were detected in stromal cells, glandular epithelial cells, endothelial and smooth muscle cells. This was low during the menstrual and proliferative phases but increased during the entire secretory phase. However, by far the most dominant staining was seen in the decidualized stromal cells late in the cycle. In contrast, the specific IL-11r chain and the signal transducing element, gp 130, were expressed throughout the cycle with minimal variation. When the expression and localization of IL-11 were examined in relation to PRL and LIF between days 19–28 of secretory phase endometrium, IL-11 expression in decidualizing stromal cells preceded PRL but followed the maximal expression of LIF in the glands.
The increase in IL-11 staining intensity from the mid-secretory phase coincides with the `implantation window', the period of endometrial receptivity to implantation (Tabibzadeh and Babaknia, 1995), supporting a possible role for IL-11 in implantation in primates. This is also the stage when the stromal cell decidualization is initiated, suggesting a possible function for IL-11 in decidualization, similar to that in the mouse. Maximal staining of IL-11 was shown by the decidual cells later in the cycle. The decidualization of endometrial stromal cells begins in areas close to the spiral arterioles during the secretory phase and interestingly the endothelial and smooth muscle cells situated in close proximity to decidual cells also showed high IL-11 immunoreactivity during the late secretory phase.
The cyclical variation in IL-11 immunoreactivity suggests direct or indirect regulation by ovarian steroids. However, local factors including cytokines are likely to be involved as these are well known to stimulate the secretion of other cytokines. For example, IL-1 stimulates IL-6 production by cultured endometrial epithelial cells (Laird et al., 1994) while LIF secretion by human decidua is augmented by oestrogen and cytokines including IL-1 and TNF (Sawai et al., 1997). Therefore there appears to be a network of cytokines coordinating their effects within the endometrium. The expression of IL-11 mRNA has been demonstrated previously in endometriotic and eutopic tissues by RT–PCR (Noble et al., 1996).
The findings of the specific cell types showing IL-11 immunoreactivity were verified in most instances by in-situ hybridization studies demonstrating mRNA in the same cell types. One exception however, was that IL-11 gene expression in the glandular epithelial cells in the secretory phase tissue was low compared to the staining intensity of immunoreactive IL-11 suggesting that the immunoreactive IL-11 may be bound to its receptor on the glandular epithelium. However, this remains to be verified as the cellular localization of IL-11R has yet to be established.
IL-11 first binds to the specific low affinity IL-11R subunit, then recruits the signal-transducing receptor component gp130; gp130 can also dimerise with the ligand-receptor complexes for LIF (Gearing et al., 1992), IL-6 (Murakami et al., 1993) and oncostatin M (Ichihara et al., 1997). IL-11R mRNA was present in the human endometrium and did not change throughout the cycle reflecting the expression pattern in the mouse (Robb et al., 1998). The signalling component, gp130, has been examined previously in relation to studies examining LIF and IL-6 expression in the endometrium. Transcripts of gp130 examined by in-situ hybridization were detected only in the glandular and luminal epithelium showing a similar pattern of expression to that of LIF (Cullinan et al., 1996). However, in another study, stromal cells isolated and cultured from either proliferative or secretory phase endometrial tissue were shown by RT–PCR to express gp130 mRNA (Yoshioka et al., 1999); in vivo the mRNA and protein levels of this component may be very low. IL-6 inhibits (Zarmakoupis et al., 1995; Yoshioka et al., 1999) and LIF stimulates (Salamonsen et al., 1997) the proliferation of endometrial stromal cells in culture demonstrating that functional gp130 must be expressed by these cells. In the present study gp130 was expressed throughout the menstrual cycle with little variation similar to that observed in the mouse (Robb et al., 1998), although its cellular location was not determined.
The differentiation process of endometrial stromal cells into decidual cells is controlled by a highly synchronized activation of specific genes (Tabibzadeh and Babaknia, 1995) and results in the co-ordinated expression of numerous new products (Tang et al., 1994). Therefore the sequence of appearance of molecules in endometrial tissue is important when examining the preparation of a receptive endometrium for implantation and can give an indication of which molecules are driving the process. PRL is a commonly used marker of decidualization and is present in the endometrium during the mid- to late secretory phase of the menstrual cycle (Bryant-Greenwood et al., 1993).
IL-11, PRL and LIF mRNA expression were examined by in-situ hybridization in sequential sections from mid- and late secretory phase tissue. IL-11 and PRL mRNA expression have not been previously examined by in-situ hybridization throughout the menstrual cycle. IL-11 mRNA expression preceded that of PRL mRNA. Decidual cells predominantly expressed PRL whereas the IL-11 transcript was produced by a greater variety of cells. This may reflect different functions at different stages of the menstrual cycle and actions on the differentiation process in different cells. The immunohistochemical results for PRL and IL-11 only partly reflected the mRNA expression data. PRL immunolocalized to both decidual cells and glandular and luminal epithelial cells in the late secretory phase, as previously demonstrated (Bryant-Greenwood et al., 1993), whereas mRNA transcripts were only present in decidual cells, suggesting that PRL of decidual origin may be bound to receptors on the epithelial cells. In support of the present data are studies in first trimester decidua, which have demonstrated PRL mRNA expression only in decidual cells (Tadokoro et al., 1995).
The results presented here also show that IL-11 gene expression precedes that of PRL in the cycling endometrium suggesting that IL-11 may be involved at an earlier stage of the decidualization process than PRL.
LIF mRNA expression in the endometrium has been demonstrated previously to occur between days 18 and 28 of the cycle (Cullinan et al., 1996; Vogiagis et al., 1996), in agreement with the current study. LIF expression was maximal in early to mid secretory phase tissue in accordance with studies demonstrating that primary cultures of epithelial cells from early secretory tissue secrete significantly higher amounts of LIF compared with tissue cultured from late secretory tissue (Laird et al., 1997). Although LIF is expressed only in the epithelium, this occurs earlier than both IL-11 and PRL indicating that LIF is involved at an earlier stage in the process of preparing a receptive endometrium for implantation. The sequence of LIF preceding IL-11 in vivo in the human is in accord with peri-implantation events in the mouse (Robb et al., 1998). The different cellular sources of IL-11 and LIF and the variation in the time of the cycle when they are expressed must reflect differences in function between the cytokines. Since IL-11 and LIF use a common signal transducer, gp130, reducing the competition for gp130 between the two cytokines through expression at different times and in different cells would be highly favourable for signal transduction.
The sequential appearance of LIF, IL-11 and PRL in the secretory endometrium, suggests quite different regulation of the three genes and different functions in preparation of the endometrium for implantation. Different regulatory mechanisms are most likely involved in the expression of each.
The critical nature of IL-11 for decidualization in the mouse and its expression pattern in the human strongly suggests a role for this cytokine in decidualization. IL-11 may play an autocrine or paracrine role in the differentiation process leading to the decidualization of stromal cells, therefore allowing for successful establishment of pregnancy. Studies are currently underway examining in more detail the role of IL-11 in this process.
Acknowledgments
We are grateful to Professor Gabor Kovacs and his patients for the provision of endometrial tissue, and to Cathy Canny and Jennifer McLaren for collection of the tissue. Dr Ewan Wallace (Department of Obstetrics and Gynecology, Monash University, Victoria, Australia) kindly provided placental tissue. We thank Sue Panckridge for assistance with the illustrations and Sam Park for assistance in preparing the manuscript. ED was supported by The Contraceptive Research and Development (CONRAD) Program, USA, LAS and LR by the National Health and Medical Research Council of Australia and LR by The Sylvia and Charles Viertel Charitable Foundation, Australia.
Notes
3 To whom correspondence should be addressed at: Prince Henry's Institute of Medical Research, PO Box 5152, Monash Medical Centre, Clayton 3168, Victoria, Australia. E-mail: evdokia.dimitriadis{at}med.monash.edu.au 
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Submitted on April 4, 2000; accepted on July 12, 2000.
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  J. S. Fitzgerald, T. G. Poehlmann, E. Schleussner, and U. R. Markert Trophoblast invasion: the role of intracellular cytokine signalling via signal transducer and activator of transcription 3 (STAT3) Hum. Reprod. Update, April 17, 2008; (2008) dmn010v1. [Abstract] [Full Text] [PDF]
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W. V. Ingman and R. L. Jones Cytokine knockouts in reproduction: the use of gene ablation to dissect roles of cytokines in reproductive biology Hum. Reprod. Update, March 1, 2008; 14(2): 179 - 192. [Abstract] [Full Text] [PDF]
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 T. Ding, H. Song, X. Wang, A. Khatua, and B. C Paria Leukemia inhibitory factor ligand-receptor signaling is important for uterine receptivity and implantation in golden hamsters (Mesocricetus auratus) Reproduction, January 1, 2008; 135(1): 41 - 53. [Abstract] [Full Text] [PDF]
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 P. Paiva, L. A. Salamonsen, U. Manuelpillai, C. Walker, A. Tapia, E. M. Wallace, and E. Dimitriadis Interleukin-11 Promotes Migration, But Not Proliferation, of Human Trophoblast Cells, Implying a Role in Placentation Endocrinology, November 1, 2007; 148(11): 5566 - 5572. [Abstract] [Full Text] [PDF]
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 N. Tawadros, L.A. Salamonsen, E. Dimitriadis, and C. Chen Facilitation of decidualization by locally produced ghrelin in the human endometrium Mol. Hum. Reprod., July 1, 2007; 13(7): 483 - 489. [Abstract] [Full Text] [PDF]
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E. Dimitriadis, C. Stoikos, Y.-L. Tan, and L. A. Salamonsen Interleukin 11 Signaling Components Signal Transducer and Activator of Transcription 3 (STAT3) and Suppressor of Cytokine Signaling 3 (SOCS3) Regulate Human Endometrial Stromal Cell Differentiation Endocrinology, August 1, 2006; 147(8): 3809 - 3817. [Abstract] [Full Text] [PDF]
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 Y. Seval, H. Cakmak, U. A. Kayisli, and A. Arici Estrogen-Mediated Regulation of p38 Mitogen-Activated Protein Kinase in Human Endometrium J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2349 - 2357. [Abstract] [Full Text] [PDF]
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E. Dimitriadis, C.A. White, R.L. Jones, and L.A. Salamonsen Cytokines, chemokines and growth factors in endometrium related to implantation Hum. Reprod. Update, November 1, 2005; 11(6): 613 - 630. [Abstract] [Full Text] [PDF]
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H. Cakmak, F. Schatz, S.-T. J. Huang, L. Buchwalder, M. Rahman, A. Arici, and C. J. Lockwood Progestin Suppresses Thrombin- and Interleukin-1{beta}-Induced Interleukin-11 Production in Term Decidual Cells: Implications for Preterm Delivery J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5279 - 5286. [Abstract] [Full Text] [PDF]
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C.A. White, E. Dimitriadis, A.M. Sharkey, and L.A. Salamonsen Interleukin-11 inhibits expression of insulin-like growth factor binding protein-5 mRNA in decidualizing human endometrial stromal cells Mol. Hum. Reprod., September 1, 2005; 11(9): 649 - 658. [Abstract] [Full Text] [PDF]
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E. Dimitriadis, C. Stoikos, M. Baca, W. D. Fairlie, J. E. McCoubrie, and L. A. Salamonsen Relaxin and Prostaglandin E2 Regulate Interleukin 11 during Human Endometrial Stromal Cell Decidualization J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3458 - 3465. [Abstract] [Full Text] [PDF]
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N. Karpovich, P. Klemmt, J. H. Hwang, J. E. McVeigh, J. K. Heath, D. H. Barlow, and H. J. Mardon The Production of Interleukin-11 and Decidualization Are Compromised in Endometrial Stromal Cells Derived from Patients with Infertility J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1607 - 1612. [Abstract] [Full Text] [PDF]
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K. Y Lee and F. J DeMayo Animal models of implantation Reproduction, December 1, 2004; 128(6): 679 - 695. [Abstract] [Full Text] [PDF]
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U. von Rango, J. Alfer, S. Kertschanska, B. Kemp, G. Muller-Newen, P.C. Heinrich, H.M. Beier, and I. Classen-Linke Interleukin-11 expression: its significance in eutopic and ectopic human implantation Mol. Hum. Reprod., November 1, 2004; 10(11): 783 - 792. [Abstract] [Full Text] [PDF]
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 E. Garzia, S. Borgato, V. Cozzi, P. Doi, G. Bulfamante, L. Persani, and I. Cetin Lack of expression of endometrial prolactin in early implantation failure: a pilot study Hum. Reprod., August 1, 2004; 19(8): 1911 - 1916. [Abstract] [Full Text] [PDF]
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I. Classen-Linke, G. Muller-Newen, P.C. Heinrich, H.M. Beier, and U. von Rango The cytokine receptor gp130 and its soluble form are under hormonal control in human endometrium and decidua Mol. Hum. Reprod., July 1, 2004; 10(7): 495 - 504. [Abstract] [Full Text] [PDF]
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 E. P. Tierney, S. Tulac, S.-T. J. Huang, and L. C. Giudice Activation of the protein kinase A pathway in human endometrial stromal cells reveals sequential categorical gene regulation Physiol Genomics, December 16, 2003; 16(1): 47 - 66. [Abstract] [Full Text] [PDF]
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N. Underhill-Day, L. A. McGovern, N. Karpovich, H. J. Mardon, V. A. Barton, and J. K. Heath Functional Characterization of W147A: A High-Affinity Interleukin-11 Antagonist Endocrinology, August 1, 2003; 144(8): 3406 - 3414. [Abstract] [Full Text] [PDF]
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N. Karpovich, K. Chobotova, J. Carver, J. K. Heath, D. H. Barlow, and H. J. Mardon Expression and function of interleukin-11 and its receptor {alpha} in the human endometrium Mol. Hum. Reprod., February 1, 2003; 9(2): 75 - 80. [Abstract] [Full Text] [PDF]
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B.A. Cork, E.M. Tuckerman, T.C. Li, and S.M. Laird Expression of interleukin (IL)-11 receptor by the human endometrium in vivo and effects of IL-11, IL-6 and LIF on the production of MMP and cytokines by human endometrial cells in vitro Mol. Hum. Reprod., September 1, 2002; 8(9): 841 - 848. [Abstract] [Full Text] [PDF]
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E. Dimitriadis, L. Robb, and L.A. Salamonsen Interleukin 11 advances progesterone-induced decidualization of human endometrial stromal cells Mol. Hum. Reprod., July 1, 2002; 8(7): 636 - 643. [Abstract] [Full Text] [PDF]
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H.-F. Chen, C.-Y. Lin, K.-H. Chao, M.-Y. Wu, Y.-S. Yang, and H.-N. Ho Defective Production of Interleukin-11 by Decidua and Chorionic Villi in Human Anembryonic Pregnancy J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2320 - 2328. [Abstract] [Full Text] [PDF]
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