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Prince Henry’s Institute of Medical Research (E.D., C.S., L.A.S.), Clayton, Victoria 3168, Australia; and The Walter and Eliza Hall Institute of Medical Research (M.B., W.D.F., J.E.M.), Parkville, Victoria 3053, Australia
Address all correspondence and requests for reprints to: Dr. Eva Dimitriadis, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, VIC 3168, Australia. E-mail: evdokia.dimitriadis{at}phimr.monash.edu.au.
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Abstract |
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Introduction |
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IL-11 is one of the few molecules identified to be obligatory for decidualization and implantation in the mouse (7). It signals via a heterodimeric complex of IL-11 receptor-
(IL-11R) and glycoprotein 130 (8). IL-11 secretion is stimulated by cAMP in a variety of cell types and has also been shown to advance in vitro progesterone-induced decidualization of human endometrial stromal cells (HESC) (5). Furthermore, up-regulation of IL-11 mRNA was detected by gene array during in vitro decidualization of endometrial stromal cells (9). IL-11 and IL-11R immunolocalize in decidualized stromal cells of mid-late secretory-phase endometrium in the human, demonstrating a local source for action (10, 11).
Although many molecules enhance progesterone-induced decidualization, only cAMP and RLX are known to stimulate HESC decidualization in vitro, independent of progesterone. RLX stimulates decidualization and intracellular cAMP levels in HESC (12, 13), and there is evidence to suggest that cAMP is involved in initiating decidualization of HESC by priming cells to the action of progesterone (14). cAMP is produced during progesterone-induced decidualization, and sustained cAMP levels are indeed necessary for decidualization to progress (15). Furthermore, the recently identified RLX receptor, LGR7, mRNA and protein are expressed by human endometrium and do not appear to be temporally regulated (16, 17). However, the RLX-deficient female mouse is fertile, suggesting either that RLX may not be absolutely required for implantation in the mouse or that its role in implantation may be to act as a mediator of other factors (18). Thus, RLX’s role in implantation may be redundant.
PG are synthesized from arachidonic acid by the actions of phospholipase A2, followed by cyclooxygenases (COX). PGE2 is synthesized and secreted by secretory-phase endometrial tissue and enhances progesterone-induced decidualization of HESC (3, 19). Studies in the rat have identified the importance of PGE2 in implantation and decidualization, whereas up-regulation of phospholipase A2 and PGE2 receptor mRNA occurs during the window of implantation, suggesting prostaglandin biosynthesis and action are important for uterine receptivity (20, 21). PGE2 stimulates IL-11 secretion from a variety of cell types, suggesting a possible interaction in endometrial stromal cells (22).
Although many factors enhance decidualization in humans, the mechanisms by which this occurs are poorly understood. IL-11 enhances progesterone-induced decidualization, but the mechanisms by which IL-11 itself is regulated during this process are not known. IL-11, RLX, and PGE are expressed by decidualized stromal cells, and each separately enhance decidualization. We hypothesized that two known generators of cAMP, RLX and PGE2, enhance decidualization through regulating IL-11. In this study, we investigated the effect of RLX and PGE2 on regulation of IL-11 mRNA expression and IL-11 secretion both in nondecidualized and decidualized HESC. Furthermore, we examined the effect of blocking IL-11 action on RLX and PGE2-induced decidualization.
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Subjects and Methods |
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Endometrial biopsies (n = 14 for short-term cell cultures, and n = 6 for long-term cell cultures) were collected at curettage from women who were scheduled for tubal ligation or were undergoing testing for tubal patency. Tissues were assessed by a pathologist and had no obvious endometrial pathology. The women had no steroid treatment or other medication for at least 2–3 months before the collection of tissue. Informed consent was obtained. Monash Medical Centre Human Ethics Committee approved the protocols.
Stromal cell isolation and culture
HESC were isolated from tissue by enzymatic digestion and filtration as described previously (5). This produces more than 95% pure stromal cell cultures, determined by analysis of vimentin and cytokeratin expression (23). Cells were plated at a density of 2.5 x 105cells per well in 24-well plates, grown to confluency in DMEM and Ham’s F12 medium (1:1) (Trace Biosciences, Sydney, Australia), supplemented with 1% penicillin, streptomycin, and fungizone (Commonwealth Serum Laboratories, Melbourne, Australia) and 10% charcoal-stripped fetal calf serum (Trace Biosciences). Experiments were conducted in medium containing 2% charcoal-stripped fetal calf serum. For each treatment group, cells were photographed for morphological analysis at required times. At the end of each experiment, cell number and viability were assessed by trypan blue exclusion unless otherwise specified. Media were assayed for prolactin (PRL) and/or IL-11, as appropriate (see below).
In vitro decidualization
HESC were decidualized as previously described (5, 6). HESC (cultures from individual endometrial biopsies; n = 6) were incubated with combinations of either 0.5 mM 8-bromo-cAMP (Sigma Chemical Co., St. Louis, MO), 100 ng/ml porcine RLX (a gift from Prof. G. Tregear, Howard Florey Institute, Melbourne, Australia), 10–5 M PGE2, or 10–8 M 17ß-estradiol (E) (Sigma) plus 10–7 M medroxyprogesterone acetate (P) (Sigma) (E+P) in duplicate wells for 8 d with media collection and replenishment every 48 h. For some cell cultures, medium was collected after 24 h (d 1). Cells were also cultured with an IL-11 signaling inhibitor, W147AIL-11, a mutant of human IL-11 with a tryptophan
alanine substitution at position 147 (24, 25) at a concentration of 4.4 µg/ml.
In vitro short-term cultures
HESC (cultures from individual endometrial biopsies; n = 3 or 6 per experiment) in duplicate wells were treated with porcine RLX (25–100 ng/ml); human H2 RLX (100 ng/ml; a gift from Dr. L. Parry, Department of Zoology, Melbourne University, Melbourne, Australia; and Connetics Corp., Palo Alto, CA); PGE2 (Sigma) (10–9 to 10–4 M); the specific cAMP/protein kinase A (PKA) inhibitor (26) adenosine-3',5'-cyclic monophosphorothioate, Rp-isomer (rp-cAMPs) (Sigma) (10–9 to 10–4 M); or indomethacin (indo), a COX1 and -2 inhibitor (Sigma) (10–9 to 10–4 M), for 24 h. For the final experiments, the following optimal dose for each reagent was selected: porcine RLX, 100 ng/ml; PGE2,10–5 M; rp-cAMPs, 10–5 M; indo, 10–5 M; cAMP, 0.5 mM; E, 10–8 M; and P, 10–7 M. Control (untreated) wells received vehicle alone.
PRL and IL-11 assays
PRL production by HESC was assayed in duplicate by ELISA (Bioclone Australia Pty. Ltd., Sydney, Australia) to determine the extent of decidualization (5). Media collected at d 1 of decidualization were concentrated 5-fold for PRL measurement. A quality control sample (culture medium from a single endometrial cell culture) was included in every assay. The lower detection limit of the assay was 50 mIU/liter. The inter- and intraassay variabilities were 5.3 and 3.0%, respectively. IL-11 secreted from stromal cells was assayed by ELISA (R&D Systems Inc., Minneapolis, MN) as previously described (5). Quality control samples were included in every assay to monitor precision. The lower detection limit of the assay was 15 pg/ml, and inter- and intra–assay variabilities were 7.1 and 2.8%, respectively. Results were expressed as percent change from untreated cells (baseline) because of the large variability in absolute values between individual cell preparations.
RNA extraction and purification
Total RNA was extracted from endometrial samples using RNeasy Minikit (QIAGEN Sciences, Germantown, MD), according to manufacturer’s instructions. All samples were treated with RNase-free DNase (Ambion, Austin, TX) to remove the possibility of genomic DNA contamination. RNA samples were then analyzed by spectrophotometry to determine RNA concentration, yield, and purity.
RNA concentrations were also analyzed by Ribogreen fluorescence RNA assay (Molecular Probes, Eugene, OR). RNA samples were diluted to approximately 20 ng/µl based on spectrophotometric readings and analyzed in a 96-well plate, in conjunction with a standard curve of serially diluted rRNA (Molecular Probes) from 0–80ng/well, by addition of Ribogreen fluorescent dye at a dilution of 1:500. This assay gave an intraassay coefficient of variation, as defined by the repeated analysis of a single RNA sample, of 3.3% (n = 6) and an interassay variation of 10.3% (n = 6).
Real-time RT-PCR
Standards for real-time PCR were generated by conventional PCR. A representative endometrial RNA sample (1 µg) was reverse transcribed using avian myeloblastosis mosaic virus reverse transcriptase (Promega, Madison, WI) and 100 ng random hexanucleotide primers (Amersham Biosciences, Piscataway, NJ), and the cDNA generated was subsequently amplified by PCR (Hybaid Express Block Cycler, ThermoHybaid, Ashford, UK): 95 C for 1 sec, 65 C for 1 sec, and 72 C for 1 sec for 40 cycles. The product was electrophoresed on a 2% agarose gel, the bands excised and cDNA purified using UltraClean GelSpin columns (MoBio Laboratories Inc., Solana Beach, CA). The resultant PCR-generated cDNA was quantitated by spectrophotometry, sequenced to confirm identity, and thereafter used as a standard for real-time RT-PCR.
Real-time RT-PCR for IL-11 was performed using Light Cycler (Roche, Mannheim, Germany) on RNA isolated from cells in duplicate treated for 24 h with E, E+P, RLX, PGE2, RLX+E+P, PGE2+E+P, cAMP, and medium-only control (n = 2 separate cultures). RNA samples were reverse transcribed as described above in duplicate to minimize the inherent variability of this technique. PCR amplification of 4 µl cDNA (diluted 1:5) was performed with addition of a MasterMix (Roche), which included SYBR Green I, dNTPs, Taq enzyme, and optimized concentrations of MgCl2 and IL-11-specific primers developed previously in our laboratory (5). The specific primers for IL-11 were as follows: 5'-GTGGCCAGATACAGCTGTCGC-3' and 5'-GGTAGGACAGTAGGTCCGCTC-3' (Sigma Genosys Australia Pty. Ltd., Castle Hill, Australia; and Invitrogen Life Technologies, Mount Waverly, Australia) and used at a concentration of 0.5 pmol/µl. An initial denaturing step was performed for 10 min at 95 C, before 40 cycles of 95 C for 15 sec, 65 C for 5 sec, and 72 C for 10 sec. An additional stage at 86 C for 5 sec was included before acquisition of fluorescence, to exclude quantitation of primer dimers.
mRNA expression was quantitated by performing the log-linear amplification phase with a four-point standard curve (standards were serially diluted 1:10). At the end of each program, melting-curve analysis was carried out to ensure specificity of the reaction products. The sizes of the products were also confirmed by gel electrophoresis for selected samples. Data were normalized using the expression of a housekeeping gene (18S) (0.5 pmol/µl) with primers 5'-CGGCTACCACATCCAAGGAA-3' and 5'-GCTGGAATTACCGCGGCT-3' (Sigma). PCR amplification of 4 µl cDNA (diluted 1:200) combined with MasterMix (Roche) was performed: 35 cycles of 95 C for 15 sec, 60 C for 5 sec, and 72 C for 10 sec, at which point fluorescence was measured. Amplified IL-11 mRNA in stimulated cells was calculated by normalizing to the amplification of 18S and then expressing the normalized values as percent change from unstimulated controls (controls were defined as 100%).
Statistical analysis
Data were expressed as mean ± SEM. Some data were analyzed by Student’s t test (PRL and IL-11 levels vs. control during cAMP-induced decidualization and IL-11 secretion after treatment with RLX or PGE2 compared with untreated controls). All other data were analyzed by ANOVA followed by Tukey’s post hoc test. A value of P < 0.05 was considered statistically significant.
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Results |
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We have previously shown that IL-11 enhances P-induced decidualization. In the present study, we showed that cAMP-induced decidualization stimulated IL-11 and PRL secretion from the cells (Fig. 1
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). PRL was below the level of detection at d 0 in all wells (data not shown). At d 8 of culture, PRL levels in culture medium from cAMP-treated cells were 58 ± 12 mU/3 x 105 cells.
Conditioned media from cells decidualized with cAMP were assayed for IL-11. IL-11 concentrations were significantly higher from d 2 of culture compared with non-cAMP-treated controls (Fig. 1). In contrast, IL-11 secreted from control cultures did not increase above d 0 levels (results not shown). At d 8 of culture, IL-11 secretion was higher from cAMP-decidualized stromal cells compared with nondecidualized controls (118 ± 27 vs. 16 ± 5 pg/3 x 105 cells; P < 0.05). Viable cell number was assessed at d 8 and did not differ significantly between wells (3.9 ± 0.2 vs. 4.1 ± 0.6/3 x 105 cells untreated vs. cAMP-treated, respectively; P < 0.05).
Effect of RLX, PGE2, rp-cAMPs, and indo on IL-11 secretion by HESC
Having shown that IL-11 is secreted during cAMP-induced decidualized stromal cells and enhances P-induced decidualization, we examined what factors regulate IL-11 in the absence of P.
Dose-response experiments.
Stromal cells cultured with porcine RLX for 24 h showed a dose-dependent increase in IL-11 secretion between doses of 25 and 100 ng/ml and no further increase with 200 ng/ml (results not shown). IL-11 secretion from stromal cells cultured with 100 ng/ml of either porcine RLX or recombinant human (rhu)RLX did not differ; however, both were higher than control (Fig. 2). IL-11 secretion from stromal cells did not change with addition of PGE2 at 10–8 or 10–7 M but increased at both 10–6 and 10–5 M compared with control (P < 0.05) (Fig. 3) and did not increase further at higher doses of PGE2 (results not shown). Concentrations of 100 ng/ml RLX and 10–5 M PGE2 were selected for subsequent studies.
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Experiments using optimal doses.
Treatment of HESC with rp-cAMPs for 24 h reduced IL-11 secretion compared with controls (P < 0.05), whereas addition of porcine RLX or PGE2 increased IL-11 secretion (P < 0.01 and P < 0.05, respectively) compared with controls (Fig. 4). Cotreatment of cells with rp-cAMPs and RLX reduced the IL-11 response to RLX (P < 0.05), but IL-11 still remained higher than in control wells (P < 0.01). By contrast, cotreatment with rp-cAMPs and PGE2 reduced the IL-11 response to PGE2 to levels similar to that observed for rp-cAMPs treatment alone, and this was also significantly reduced compared with controls (P < 0.05) (Fig. 4). Addition of indo to endometrial stromal cells reduced IL-11 secretion relative to untreated controls (P < 0.05), whereas cotreatment of cells with indo and PGE2 increased IL-11 secretion (P < 0.05) although not to the levels of PGE2-treated cells (Fig. 4). Cotreatment of cells with RLX and indo did not alter IL-11 secretion compared with cells treated with RLX alone (Fig. 4).
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RLX and PGE2 enhance PRL secretion during P-induced decidualization. Having shown that both RLX and PGE2 stimulated IL-11 secretion we aimed to determine whether blocking IL-11 action reduced PRL secretion stimulated by RLX and PGE2.
HESC did not secrete PRL at d 1 of culture after treatment with E, E+P, RLX, PGE2, or any combination of these treatments (results not shown). However, when cells were treated with E+P for 8 d, there was an increase in PRL secretion compared with cells treated with E alone as reported previously (Fig. 5) (5). RLX alone or in combination with PGE2 also stimulated PRL secretion on d 8, to a level similar to that achieved with E+P alone (Fig. 5). PGE2 alone did not stimulate production of PRL (not shown), although when added in conjunction with E+P, PRL levels were significantly elevated above levels achieved with E+P alone. Combined treatments of RLX and E+P also resulted in levels of PRL that were significantly higher than those achieved by either treatment on its own. The combination of all three (RLX, PGE2, and E+P) resulted in PRL levels higher than those achieved with PGE2 and E+P but not higher than those resulting from RLX and E+P treatment. When the IL-11 signaling inhibitor W147AIL-11 was added to cultures with a combination of E+P and either RLX or PGE2, PRL secretion from the cells was significantly reduced (Fig. 5). Culture of cells with cAMP resulted in levels of PRL similar to those of cells cultured with RLX+E+P or cAMP+E+P. However, cells cultured with RLX+PGE2+E+P secreted higher levels of PRL compared with cells cultured with cAMP (P < 0.05) (Fig. 5). Table 1 shows PRL secretion from cells at d 8 of culture normalized to cell number from one representative patient.
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; all were confluent monolayers. The nondecidualized E control cells and those treated with PGE2 alone appeared elongated and spindle shaped (Fig. 6, A and C). The PRL-secreting cells appeared pavement-like, characteristic of decidualized cells from all treatment groups (Fig. 6, B and D–I). The cells that secreted the highest amount of PRL (Fig. 5) consistently showed some loss of distinct cell borders (Fig. 6, E, G, and I), a characteristic previously demonstrated in cells treated with E+P+IL-11 (5).
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At d 1 of the decidualization time course (before secretion of PRL), IL-11 secretion from HESC was increased after culture with RLX, PGE2, RLX+PGE2, or cAMP compared with E+P (P < 0.05) (Fig. 7A). In contrast, addition of E+P to the cultures with RLX, PGE2, or cAMP attenuated any response, and IL-11 levels were the same as those seen in E+P alone (P < 0.05) (Fig. 7A). Furthermore, RLX-treated cells secreted higher amounts of IL-11 compared with E+P-, RLX+E+P-, PGE2-, RLX+PGE2+E+P-, and E+P+cAMP-treated cells (P < 0.05) (Fig. 7A).
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). Table 1 shows IL-11 secretion from cells at d 8 of culture normalized to cell number from one representative patient. Effect of PGE2 and RLX on steady-state IL-11 mRNA
Real-time RT-PCR was conducted to determine the regulation of IL-11 mRNA expression. IL-11 mRNA expression by HESC was increased after addition of either RLX, PGE2, or cAMP relative to untreated cells (Fig. 7A), in agreement with the secretion of IL-11 by similarly treated cells (Fig. 8). Addition of P to cell cultures containing RLX or PGE2 inhibited this response again in accord with IL-11 release from similar cultures.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There is increasing evidence that IL-11 has an important function in implantation in humans. Several studies have identified both IL-11 and IL-11R mRNA and protein in decidual cells from late-secretory phase and early pregnant endometrium (5, 11, 29, 30, 31). Furthermore, invasive trophoblast cells are a source of IL-11 and IL-11R during early pregnancy in primates, suggesting an involvement in placentation (29, 30). Similarly, PGE2 immunolocalizes in human endometrial stroma during the late-secretory phase (19) and in decidual cells early after implantation in the mouse, similar to the spatial and temporal localization of IL-11 mRNA (7, 32). Furthermore, PGE2 enhances decidualization of HESC (3). Thus, both human and rodent localization studies indicate a possible interaction between the two molecules. RLX is also synthesized and secreted by HESC (33) and stimulates decidualization of HESC in vitro (12), whereas in the rhesus monkey, RLX treatment results in a more decidualized morphology of the uterus compared with vehicle-treated monkey uterus (34).
Decidualization is a complex process of continuum, and although little is known about its mechanisms, it has been proposed that cAMP and PKA are necessary for decidualization in vitro by sensitizing endometrial stromal cells to the action of progesterone (2, 35). Interestingly, RLX and PGE2, which elevate intracellular cAMP levels, enhance progesterone-induced decidualization (2, 3). Furthermore, PGE2 stimulates decidualization possibly via cAMP in the rat (36). In the current study, cAMP stimulated IL-11 mRNA expression and secretion during decidualization, in agreement with a recent microarray study revealing that IL-11 mRNA expression was one of the most abundantly up-regulated genes after treatment of HESC with cAMP (37).
The present study demonstrated that both RLX and PGE2 stimulated IL-11 mRNA expression and release by endometrial stromal cells via cAMP/PKA. Furthermore, a recent study (16) showed that inhibiting phosphodiesterase 4, which normally blocks cAMP, increases cAMP production in HESC, raising the possibility that phosphodiesterase 4 may also indirectly regulate IL-11 secretion. Whether other decidualizing stimuli, such as CRH (4), which act through cAMP, also stimulate IL-11 secretion remains to be established. Although we did not measure PGE2 in this study, a local source of PGE2 is likely in vivo; HESC isolated from secretory-phase endometrium secrete PGE2 in vitro (38). cAMP is involved in PGE2 signal transduction through EP2 and EP4 receptors, which are expressed by endometrial stromal cells (19, 39), and the stromal cell response to PGE2 in the present study suggests functional receptors were present. Furthermore, PGE2 can act via cAMP and has been shown to stimulate cAMP generation from secretory-phase endometrial tissue, supporting our data (19, 39).
It is interesting that there are very different effects of progesterone on IL-11 mRNA expression and protein secretion depending on whether the cells are nondecidualized or decidualized. In nondecidualized cells (untreated or treated with RLX or PGE2), progesrerone down-regulated IL-11, whereas once the cells were decidualized, this effect was much smaller. The reason for this change of responsiveness is not yet clear.
Blocking IL-11 signaling (with an inhibitor) in cells that were decidualized with PGE2+P or RLX+P reduced PRL secretion near to control levels. This strongly suggests that RLX and PGE2 enhance decidualization via regulation of IL-11.
In the current study, the COX inhibitor indo reduced IL-11 secretion from the cells, indicating that endogenous prostaglandins may be the stimulus. In the mouse, loss of COX2 activity delays decidualization within the first 24 h of implantation (40) and it is possible that loss of COX2 activity results in lower IL-11 levels resulting in this delayed implantation; this remains to be determined. Prostaglandins have been implicated in decidualization and implantation both in the human and rat (21, 41), whereas prostacyclin (PGI2), has also been implicated in these processes in the mouse (42). PGI2, like PGE2, may contribute by stimulating IL-11 secretion from endometrial stromal cells. PGI2 is found in the mouse uterus at d 4 of pregnancy, the time when the embryo implants (42); this may also be the case in the human endometrium during implantation, although this remains to be determined. In the present study, the failure of PGE2 plus indo-treated cells to secrete the same level of IL-11 seen in the absence of indo indicates that one or more additional products of COX action may also stimulate IL-11. The identity of these products and their importance in decidualization remain to be determined.
It is likely that RLX is a very early stimulus for decidualization because RLX immunolocalizes to decidualized stromal cells in human endometrium (43) and like IL-11 precedes the appearance of immunoreactive PRL in decidual cells (10). The RLX receptor LGR7 immunolocalizes in stroma of mid and late secretory-phase endometrial tissue (44). We propose that RLX and PGE2 stimulate IL-11 production by HESC in mid-late secretory-phase endometrium before PRL production is detectable, possibly initiating differentiation, and that progesterone acts to further drive the process.
In conclusion, the results of this study demonstrated that RLX, PGE2, and progesterone synergize to regulate IL-11 mRNA expression and secretion by endometrial stromal cells during decidualization. Furthermore, the data link the actions of RLX and PGE2 with the cAMP/PKA pathway, which is critical in initiating decidualization. The data strongly suggest that RLX and PGE2 drive decidualization via IL-11 production and action and further strengthen the case for the importance of IL-11 in decidualization. This indicates that targeting IL-11 may be useful in either enhancing or blocking human embryo implantation. It has widespread implications in facilitating the establishment of pregnancy and placentation or in providing a contraceptive target.
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Acknowledgments |
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Footnotes |
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First Published Online March 22, 2005
Abbreviations: COX, Cyclooxygenases; E, 17ß-estradiol; HESC, human endometrial stromal cells; IL-11R, IL-11 receptor-; indo, indomethacin; P, medroxyprogesterone acetate; PG, prostaglandin; PKA, protein kinase A; PRL, prolactin; rhu, recombinant human; RLX, relaxin; rp-cAMPs, adenosine-3',5'-cyclic monophosphorothioate, Rp-isomer.
Received June 1, 2004.
Accepted March 10, 2005.
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and tumor necrosis factor synergistically stimulate prostaglandin E2-dependent production of interleukin-11 in rheumatoid synovial fibroblasts. Arthritis Rheum 41:2004–2013[CrossRef][Medline]
immunolocalisation at primate implantation sites supports a role for IL-11 in placentation and fetal development. Reprod Biol Endocrinol 1:34[CrossRef][Medline]
in the human endometrium. Mol Hum Reprod 9:75–80
B. J Biol Chem 277:26208–26216 is crucial [correction of A2 deficiency is crucial] for ‘on-time’ embryo implantation that directs subsequent development. Development 129:2879–2889
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) for 8 d and PRL measured in cultured medium from the last 48 h of treatment. Data are mean percentage of E+P ± SEM (E+P was defined as 100%) (duplicate treatments from three separate cultures). *, P < 0.05 compared with E+P; **, P < 0.05 between groups indicated.
