Molecular Human Reproduction, Vol. 6, No. 4, 344-351,
April 2000
© 2000 European Society of Human Reproduction and Embryology
Uterine physiology |
Corticotrophin-releasing hormone (CRH) interacts with inflammatory prostaglandins and interleukins and affects the decidualization of human endometrial stroma
1 Department of Pharmacology, 2 Department of Clinical Chemistry, 3 Department of Biochemistry and 4 Department of Obstetrics and Gynecology, Medical School, University of Crete, Heraklion 71110 Greece
Abstract
The hypothalamic neuropeptide, corticotrophin-releasing hormone (CRH), which is also produced by human endometrium, has been shown to induce its decidualization in vitro. This process, induced mainly by progesterone, has characteristics of an aseptic inflammatory reaction, and is modulated by locally produced pro-inflammatory factors. In humans, prostaglandin E2 (PGE2) enhances while interleukin (IL)-1 inhibits the decidualizing effect of progesterone. The aim of the present work was to test the hypothesis that CRH might affect the decidualization of human endometrium interacting with these factors. Therefore, we studied its effects on the production of pro-inflammatory interleukins IL-1, IL-6 and of PGE2 from human endometrial stromal cells in primary culture. The results strongly suggest that CRH decidualizes stromal cells, as judged by the appearance of cytokeratins and the production of prolactin, two established markers of decidualization. In parallel to its effect on decidualization, CRH also decreased the production of PGE2, while it increased the production of IL-1 and IL-6. Exposure of endometrial stromal cells to IL-6 also caused decidualization. The data presented here suggest that endometrial CRH regulates the production of local modulators of decidualization, i.e. PGE2, IL-1 and IL-6. We postulate that, through the regulation of these factors, CRH acts as a local fine-tuner of decidualization initiated by progesterone.
corticotrophin-releasing hormone/decidualization/human endometrium/interleukins/prostaglandin E2
Introduction
Corticotrophin-releasing hormone (CRH), a hypothalamic neuropeptide (Vale et al., 1983
), is widely expressed across the reproductive tract where it serves as a paracrine modulator (Fabbri et al., 1990; Mastorakos et al., 1993, 1994). CRH is also present in multiple intra-uterine structures. Thus, during pregnancy, CRH is produced in the syncytiotrophoblast, chorion, amnion and decidua (Grino et al., 1987; Frim et al., 1988; Petraglia et al., 1992). CRH is also produced in the non-pregnant uterus (Makrigiannakis et al., 1995a, b; Mastorakos et al., 1996; Clifton et al., 1998). The role of uterine CRH is under investigation. Multiple lines of evidence attribute pro-cytokine pro-inflammatory properties to CRH (Karalis et al., 1991; Crofford et al., 1992, 1993). It now appears that the effects of CRH in the reproductive tract are carried out mainly via its pro-inflammatory properties such as in the case of ovulation, luteolysis (Mastorakos et al., 1993, 1994), and blastocyst implantation (Makrigiannakis et al., 1995b).
The differentiation process of endometrial stroma to decidua exhibits several characteristics of an aseptic inflammatory reaction (Spornitz, 1992). During decidualization, endometrial stroma is subjected to major functional changes, including an increase in vascular permeability, cell growth and remodelling of the extracellular matrix (Psychoyos et al., 1995). Additionally, it produces inflammatory factors, e.g. prostaglandin E2 (PGE2) and interleukins 1 (IL-1) and -6 (IL-6) (Tabibzadeh et al., 1989; Semer et al., 1991), many of which are assumed to play important roles in the control of this phenomenon in an autocrine/paracrine manner. Indeed, in humans, PGE2 appears to enhance, while IL-1 inhibits, the decidualization process, induced by progesterone (Kariya et al., 1991; Frank et al., 1994, 1995).
Recent experimental findings suggest that CRH may be involved in the decidualization process of human endometrial stromal cells (Ferrari et al., 1995). This paracrine action is further strengthened by reports confirming the expression of the CRH receptor (CRH-R1) on human endometrial stromal cells (DiBlazio et al., 1997). The aim of the present work was to test the hypothesis that CRH acts as a local fine-tuner of decidualization, regulating stromal cell production of prostaglandins and interleukins. The effect of CRH on stromal cell decidualization and its effects on the production of PGE2, IL-1 and IL-6 from human endometrial stromal cells in primary culture were studied, as well as the effect of IL-6 on stromal cell decidualization (which had not been studied previously in this tissue).
Materials and methods
Isolation and culture of human endometrial stromal cells
EndometriaI specimens were obtained from patients undergoing biopsy for fertility evaluation or hysterectomy. Informed consent was obtained and the study was approved by the Ethics Committee of the University of Crete, Faculty of Medicine. Only tissues deriving from normal human proliferative endometrium were used. The tissues were trimmed and minced under a laminar flow hood in Dulbecco's minimum essential medium (DMEM; Gibco) containing 1% of an antibiotic–antimycotic mixture (Grand IsIand Biological Co, Grand Island, NY, USA). Cell dispersion and isolation was carried out in DMEM supplemented with 15 mmol/l HEPES, 1% antibiotic–antimycotic mixture (Gibco) to a final concentration of 100 IU/ml penicillin and 100 µg/ml streptomycin and 10% fetal calf serum (FCS). The isolation procedure was performed as previously described (Tabanelli et al., 1992). Briefly it includes: (i) digestion of minced tissues in a water bath for 90 min at 37°C exposed to 0.25% of Type I collagenase; (ii) separation of epithelium and stroma by filtration through a 45 µm stainless steel sieve; (iii) backwashing the epithelium from the sieve, followed by pelleting by centrifugation; and (iv) separation of epithelial cells from stromal cells in the filtrate by taking advantage of the more rapid adhesion of stromal cells to plastic surfaces at 37°C. Endometrial stromal cell cultures prepared using this protocol reduced contamination by epithelial cells and leukocytes to <2%.
Endometrial stromal cells were cultured in 25 cm2 culture flasks in DMEM containing 10% FCS up to confluency. After that they were cultured in DMEM 2% FCS containing various concentrations of CRH, 
-helical-CRH, indomethacin, and their combinations. The medium was changed every 2 days and new drugs were added daily. To measure the protein content, cells were scraped and harvested in Hank's balanced salt solution (HBSS; Gibco).
Immunofluorescence of cytokeratins
Immunofluorescence microscopy was performed as previously described (Fostinis et al., 1992). Briefly, endometrial stromal cells were grown on 22x22 mm coverslips in DMEM FCS 2%. Cells were fixed and permeabilized for 20 min in an acetone–methanol (9:1 v/v) solution at room temperature, followed by two washes in phosphate-buffered saline (PBS). Cells were then incubated with the KL1 mouse monoclonal antibody against human cytokeratin (Immunotech, Paris, France) in PBS for 20 min at 4°C and washed three times for 3 min each in PBS. The dilution of the antibody was 1:100. Fluorescein isothiocyanate (FITC)-labelled goat anti-mouse immunoglobulin G (IgG) (Ortho Diagnostic Systems, New Jersey, USA) was used as second antibody. For control experiments, endometrial stromal cells were incubated with PBS without the cytokeratin antibody or with non-immune mouse serum diluted 1:100 and exposed to FITC. Fluorescence patterns were analysed under a Leitz Dialux 2 OEB microscope (Vetzar, Munich, Germany) equipped with epifluorescent illumination. Photographs were taken on Kodak CF 3200 films.
Measurement of prolactin by chemiluminescence
The culture medium was centrifuged at 800 g for 10 min and the supernatant was dried under vacuum and stored at –20°C. The prolactin content was determined using a chemiluminescence assay (Nichols Institute Diagnostics, San Francisco, USA). The assay uses a mouse monoclonal antibody to prolactin immobilized on a polystyrene bead and a goat polyclonal antibody to prolactin labelled with an acridinium ester. Acridinium esters emit light (420–430 nmol/l) upon treatment with hydrogen peroxide and an alkaline solution. The sensitivity of the assay was 0.1 ng/ml. The intra-assay coefficient of variation (CV) was 3.5% and the inter-assay CV was 7.5%. Results are expressed as ng of prolactin per mg of total cellular protein, determined on whole cellular homogenates by the Bradford method (Makrigiannakis et al., 1999a) using bovine serum albumin as standard. Results were normalized to the respective controls, i.e cells not exposed to any compound, and presented as percentiles of the control.
Measurement of PGE2 by radioimmunoassay
Measurement of the PGE2 content in the culture medium was performed by using a PGE2 (125I) radioimmunoassay system (Amersham International, London, UK). Briefly, the culture medium was centrifuged at 800 g for 10 min. Methoxyamine hydrochloride was added to the supernatant in order to convert PGE2 to its more stable, methyl oximate, derivative. The supernatant was then stored at –80°C until assayed. The sensitivity of the assay was 1.0 pg/tube. The intra-assay CV was 3.7% and the inter-assay CV was 9.7%. Results are expressed as ng of PGE2 per mg of protein, determined on whole cellular homogenates by the Bradford method, using bovine serum albumin as standard. Results were also normalized to the respective control, i.e. cells not exposed to any compound, presented as pecentiles of the control.
Measurement of interleukins by enzyme-linked immunoassay (ELISA)
Culture media and cell extracts for IL-6 and IL-1ß determination respectively were stored at –80° C until assayed. The concentrations of interleukins were measured by enzyme-linked immunosorbent assays, specific for each one of them, using a `sandwich' method (Quantikine; R and D Systems, Baltimore, USA). The results were expressed as pg of the respective cytokine per mg of total cellular protein, which were determined on whole cellular homogenates by the Bradford method using bovine serum albumin as standard. Finally, results were normalized to the respective control, i.e cells not exposed to any compound, and presented as percentiles of the control.
Statistical analysis
As it was mentioned above, results are expressed as percentage of parallel controls (i.e. cells exposed to vehicles). They correspond to the mean ± SEM of triplicates of at least six independent experiments. Statistical analysis for these data was performed by two non-parametric statistical methods (Kruskal–Wallis and Mann–Whitney tests). Statistical evaluation of non-normalized data was performed by analysis of variance.
Results
CRH induces the decidualization of endometrial stromal cells
Stromal cells, isolated from proliferative endometrium, were exposed for up to 12 days to 100 nmol/l of CRH, in the absence or presence of the CRH antagonist, -helical-CRH at 1000 nmol/l or cyclo-oxygenase (COX) inhibitor, indomethacin at 1 µmol/l. As shown in Figure 1A, CRH induced major morphological changes of stromal cells. The originally elongated spindle-shaped stromal cells were converted to round and oedematous cells, characteristics of the decidual phenotype. The decidualizing effect of CRH was confirmed by another morphological decidual marker, cytokeratins. These intermediate filament proteins are not expressed in normal stromal cells unless they differentiate to decidual cells (Heatley et al., 1996). As depicted in Figure 1B, exposure of stromal cells to 100 nmol/l of CRH for 8 days resulted in the appearance of cytokeratins, as shown by immunofluorescence staining of cytokeratin skeleton in the cytoplasm. It is important that the appearance of CRH-induced cytokeratins was completely blocked by 1 µmol/l of the CRH antagonist, -helical-CRH, but it was unaffected by 1 µmol/l of the general COX inhibitor indomethacin (Figure 2B).
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These morphological changes were accompanied by biochemical markers, specific to the decidualization process. In cultured stromal cells, CRH increased the release of prolactin, a characteristic decidual product (Tabanelli et al., 1992
), in a time- and dose-dependent manner (Figure 2A,B
). The maximal response was measured on the day 8 of exposure to 100 nmol/l of CRH, reaching an impressive 2509 ± 612% of parallel controls (n = 8, P < 0.001). It is important that the effect of CRH on prolactin secretion was completely blocked by 1 µmol/l of -helical CRH (Figure 2A), while it was not affected by 1 µmol/l of indomethacin (Figure 2B).
IL-6 induces the decidualization of endometrial stromal cells
IL-6 affected the decidualization of human endometrial stromal cells. Stromal cells were exposed to 100 nmol/l of IL-6 for up to 10 days and the decidualization process was assessed by determining the expression of cytokeratins and prolactin secretion. Similarly to CRH, IL-6 induced stroma decidualization, as judged by the appearance of cytokeratins (Figure 1B) and the stimulation of prolactin production (Figure 3). The peak effect of IL-6 on prolactin was found after exposure of stromal cells to 100 nmol/l of IL-6 for 8 days and was 306 ± 22% of control (n = 6, P < 0.02). The induction of prolactin by IL-6 was observed as early as day 2. During decidualization in vitro, prolactin induction can start early while morphological changes follow a few days later (Tabanelli et al., 1992). Cytokeratin staining of stromal cells exposed to IL-6 became evident on day 6 and stronger on day 8 (Figure 1B). Compared with CRH, the effect of IL-6 appeared to be less pronounced, as judged by the production of prolactin.
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CRH affects the production of PGE2 from human endometrial stromal cells
CRH suppressed the production of PGE2 from human endometrial stromal cells in a time- and dose-dependent fashion. Figure 4A
depicts the concentration of PGE2, expressed as percentage of the control after exposure of stromal cells to 100 nmol/l of CRH. The maximum effect was shown after 8 days and was 48 ± 12% of control (n = 8, P < 0.001). Figure 4B shows the dose–response of PGE2 to CRH. The effect of CRH on PGE2 appears to be mediated by CRH receptors since the addition of 1000 nmol/l of the CRH antagonist, -helical-CRH completely abolished it (Figure 4A,B). Incubation of stromal cells with CRH in the presence of 1 µmol/l of indomethacin resulted in complete inhibition of biosynthesis of endogenous PGE2 (Figure 4A,B). This blockage did not influence the appearance of cytokeratins (Figure 1B) or prolactin secretion (Figure 2B) suggesting that the direct effect of CRH on decidualization does not involve the production of PGE2.
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CRH affects the production of IL-6 from human endometrial stromal cells
To define the effect of CRH on IL-6, stromal cells were exposed to 100 nmol/l of CRH for up to 12 days. Figure 5
illustrates the concentration of IL-6 throughout this time period, expressed as percentage of parallel controls. CRH stimulated the concentration of IL-6 in a time-dependent manner. The maximum effect was measured on day 6, reaching 161 ± 12% of control (n = 6, P < 0.05). The effect of CRH on IL-6 is mediated by CRH receptors since the addition of 1000 nmol/l of -helical-CRH completely prevented it.
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CRH affects the production of IL-1ß from human endometrial stromal cells
CRH induced the production of IL-1ß from human endometrial stromal cells. Stromal cells were incubated with 100 nmol/l of CRH for up to 8 days then IL-1ß was measured in the cell extract. Figure 6
depicts the concentration of IL-1ß through time, presented as percentage of control. CRH increased the concentration of IL-1ß in stromal cells. The maximal effect was found on day 8, reaching 240 ± 26% of control (n = 6, P < 0.02).
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Discussion
The differentiation of human endometrial stroma to decidua is crucial in order to achieve successful implantation of the developing blastocyst. This phenomenon is under the control of cAMP, the strongest known stimulus of decidualization in the human. Endometrial cAMP is induced by almost all known decidualizing factors, including progesterone and CRH. However, it should be noted that the process of decidualization has characteristics of an aseptic inflammatory reaction. As a result, locally produced pro-inflammatory factors, e.g. prostaglandins and interleukins, may also participate, alone or in conjunction with progesterone and possibly cAMP, in the regulation of this phenomenon (Kariya et al., 1991; Frank et al., 1994, 1995; Ferrari et al., 1995). In the present study, the novel observation is reported that, during decidualization, CRH interacts with these local factors, regulating endometrial PGE2 and IL-1 and IL-6. Additionally, our data indicate IL-6 as a novel factor of decidualization.
The findings of this study show that CRH has the ability alone, in the absence of progesterone, to decidualize human endometrial stromal cells in vitro, confirming previously published data (Ferrari et al., 1995). The decidualizing effect of CRH was completely blocked by the CRH antagonist, -helical-CRH, suggesting that it is mediated via the CRH-R1 receptor, which has been shown to be expressed on human endometrial stromal cells (DiBlazio et al., 1997). These cells also express the CRH gene and synthesize its peptide product, though at very low concentrations which are pharmacodynamicaly insufficient (Petraglia et al., 1992). Indeed, stromal cells require the addition of exogenous CRH for their decidualization in vitro. However, it has recently been reported that progesterone stimulates the transcription of the CRH gene and the production of its end-product in human endometrial stromal cells (Makrigiannakis et al., 1999a). Thus, progesterone-induced stromal CRH may also contribute to CRH-dependent pathways in the decidualization process. However, it should be noted that epithelial cells of human endometrium strongly express the CRH gene (Makrigiannakis et al., 1995a), which is most probably the main source of endometrial CRH affecting decidualization in vivo.
The decidualizing effect of CRH does not appear to be affected by indomethacin, suggesting that its action does not involve the production of endogenous prostanoids. However, under the same experimental conditions, CRH inhibited the production of PGE2 in a time- and dose-dependent manner. Nevertheless, it should be noted that PGE2 appears to be required for the maintenance of decidualization in animal models, since inhibition of its synthesis by indomethacin inhibits decidualization in both rat and mouse (Psychoyos et al., 1995). In humans, PGE2 drastically enhances the decidualizing effect of progesterone, although it does not exert any effect of its own (Frank et al., 1994). The enhancing effect of PGE2 is mediated via EP2, a prostaglandin receptor, which involves activation of adenylate cyclase (Brar et al., 1997). Thus, it is possible that endometrial CRH, in addition to its direct decidualizing effect, might also modulate the decidualizing effect of progesterone through regulation of locally produced PGE2. The inhibitory effect of CRH on the production of PGE2 from human endometrial stromal cells (reported in the present study), is in agreement with similar findings regarding prostaglandin production from endothelium and fibroblasts in vitro. More specifically, it has been shown that CRH suppresses the synthesis of PGE2 from human endothelial cells and fibroblasts in culture, via inhibition of COX (Fleisher-Berkovich and Danon, 1995). However, it contrasts with the stimulatory effect of CRH on placental and decidual prostaglandins. In fact, CRH stimulates the production of PGE2 from human placental and decidual cells at term, via stimulation of the transcription of COX-2 mRNA (Jones and Challis 1990; Petraglia et al., 1995; Alvi et al., 1999). Thus, it appears that CRH may differentially regulate the synthesis of uterine PGE2. Indeed, early in pregnancy CRH inhibits the production of PGE2 from endometrial stroma, resulting in the quiescence of myometrial tone, necessary for an efficient nidation of the developing blastocyst. Later in pregnancy near term, CRH stimulates the synthesis of placental and decidual PGE2, thus enhancing cervical ripening and myometrial contractility, in preparation for parturition.
Human endometrium is one of the principal examples where local modulators of inflammation participate in normal functions. Indeed, modulators of inflammation appear to be part of the mechanisms involved in both endometrial decidualization and the implantation of the conceptus (Psychoyos et al., 1995). It is now well-established that endometrial stroma produces pro-inflammatory cytokines, including IL-1 and IL-6 (Tabibzadeh et al., 1989; Semer et al., 1991). The current findings suggest that IL-1 and IL-6 from endometrial stroma are under the positive control of CRH. Indeed, CRH stimulated the production of both cytokines from human endometrial stromal cells in culture. This action parallels the stimulatory effect of CRH on the release of both IL-1 and IL-6 from cultured human peripheral blood mononuclear cells (Singh and Leu, 1990; Leu and Singh, 1992; Angioni et al., 1993). IL-1 is a modulator of the decidualization process, blocking the differentiation of human endometrial stromal cells induced by ovarian steroids or cAMP (Kariya et al., 1991; Frank et al., 1995; Mizuno et al, 1999). The stimulatory effect of CRH on stromal IL-1 suggests that this neuropeptide affects decidualization either as a principal regulator or as a modulator of the decidualizing effect of progesterone, the hitherto dominant inducer of endometrial decidualization. It has recently been shown that progesterone induces endometrial stromal CRH (Makrigiannakis et al., 1999a). Thus, it is possible that progesterone-driven CRH may exert an inhibitory effect on endometrial decidualization through induction of a local inhibitor, IL-1, establishing a complex feedback mechanism to prevent over-stimulation of stromal cells.
It is of interest that the current data allow the inclusion of IL-6 in the group of regulators of endometrial decidualization. It was found that IL-6 induced morphological and biochemical changes of human endometrial stromal cells, characteristic of decidualization. This observation is further supported by recent findings showing that the immunoreactivity of IL-6 in both epithelial and stromal cells of human endometrium rises in the secretory phase of the menstrual cycle (Tabibzadeh et al., 1995). The mechanism of this stimulatory effect of IL-6 on the differentiation of endometrial stromal to decidual cells is unclear and needs further investigation. However, recent in-vitro findings suggest that both cAMP, and compounds generating cAMP, (including CRH, relaxin, and gonadotrophins) are all inducers of the decidualization process (Telgmann and Gellersen, 1998). Thus, it is possible that IL-6 might act as a decidualizing factor, interfering with the cAMP pathway. This hypothesis is supported by recent data showing an association between IL-6-dependent JAK/STAT signal transduction and cAMP signalling in various cell types (Kojima et al., 1996; Sengupta et al., 1996), including decidual cells (Deb et al., 1999). IL-6 has been shown to inhibit the proliferation of stromal cells in vitro (Zarmakoupis et al., 1995; Yoshioka et al., 1999). It is of note that during decidualization, endometrial stroma is subjected to major functional modifications, including changes of cell growth, apoptosis and tissue remodelling (Psychoyos et al., 1995). Thus, another mechanism by which IL-6 may propagate decidualization in vivo, is by participating in the regulation of these phenomena.
The effect of CRH on endometrial cytokines appears to be bi-directional. It has recently been shown that IL-1 and IL-6 induce the expression of CRH in endometrial cells via a prostaglandin-dependent manner (Makrigiannakis et al., 1999b). These findings strongly support the hypothesis that CRH, cytokines, and prostaglandins form a local network connecting stromal to glandular epithelial cells. This hypothesis is further strengthened by recent data showing that PGE2 induces CRH transcription in endometrial cells (Makrigiannakis et al., 1996). It is also of interest that human endometrial cells respond to IL-1 or IL-6 by a major increase of their PGE2 formation (Mitchell et al., 1991; Chen et al., 1995). These data taken together point out that endometrial CRH is an integral part of the chain of events culminating in the differentiation of endometrial stroma to decidua (Figure 7). In conclusion, these data enable us to postulate that during decidualization the following sequence of events takes place: (i) progesterone, in addition to its strong decidualizing effect, also stimulates the production of endometrial CRH; (ii) CRH participates in stromal decidualization, regulating the local modulators of this process, i.e. inhibits the enhancer PGE2, induces the inhibitor IL-1, and stimulates the inducer IL-6; and (iii) concurrently, endometrial PGE2, IL-1 and IL-6 exert a positive control of the expression of endometrial CRH, establishing a local regulatory loop.
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Acknowledgments
We would like to respectfully dedicate this work to the memory of our mentor Dr Alexandros Psychoyos. This work was supported by a grant to A.G. from the General Secretariat of Research and Technology (PENED94).
Notes
5 To whom correspondence should be addressed 
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Submitted on October 12, 1999;
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