Unité de Recherche en 1Ontogénie et Reproduction et 2 Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUL, 2705 Boul. Laurier, Ste-Foy, Québec, G1V 4G2, 3 Endocrinologie de la Reproduction Centre de Recherche de l'Hôpital St-François d'Assise and 4 Département d'Obstétrique et Gynécologie, Université Laval, Ste-Foy, Québec, G1K 7P4, Canada
5 To whom correspondence should be addressed at: Unité de Recherche en Ontogénie et Reproduction, Centre Hospitalier Universitaire de Québec (CHUL), Université Laval, 2705, Boul. Laurier, Sainte-Foy, Québec, G1V 4G2, Canada. Email: mafortier{at}crchul.ulaval.ca
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Abstract |
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Key words:
hCG/human endometrium/IL-1/MCP-1/prostaglandins
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Introduction |
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It is now widely acknowledged that PG are important regulators of female reproductive function (for a review, see Poyser, 1995). PG are produced from arachidonic acid (AA) stored in cell membrane phospholipids and liberated by phospholipases (PL). The conversion of AA to PG is catalysed by the rate-limiting enzyme cyclooxygenase (COX). Two isozymes have been identified, a constitutively expressed form COX-1 and an inducible form COX-2 (for a review, see Otto and Smith, 1995
). PGE2 and PGF2
are the two most studied prostanoids in human endometrium. The aberrant ratio of PGE2:PGF2
is associated with menstrual disorders such as dysmenorrhoea and menorrhagia (for a review, see Poyser, 1995
). In some species, an increase in endometrial prostaglandin production was observed around the peri-implantation period or at the implantation site, suggesting an important role for PG in the implantation process (for a review, see Psychoyos et al., 1995
).
Chemokines are increasingly recognized as important regulators of uterine function (for a review, see Kayisli et al., 2002). Monocyte chemoattractant protein-1 (MCP-1), a member of the beta-chemokine family, displays chemotactic activity for monocytes/macrophages, T lymphocytes, basophils and natural killer cells and recruits them into sites of inflammation (for a review, see Leonard and Yoshimura, 1990
). MCP-1 can be released by endometrial epithelial and stromal cells in culture (Arici et al., 1995
). In human endometrium, its expression was detected in a cyclical pattern during the menstrual cycle (Jones et al., 1997
). The highest level of MCP-1 is detected peri-menstrually (Arici et al., 1999
).
It has been demonstrated that in some cell types, interleukin-1 (IL-1) is able to induce both PG and MCP-1 production (Efsen et al., 2001). IL-1
is a pro-inflammatory cytokine expressed in the endometrium throughout the menstrual cycle, particularly around the time of implantation (Simon et al., 1995
). It is postulated to mediate the dialogue between the blastocyst and the endometrium in implantation (Ibid, Simon et al., 1995
). IL-1
can induce PG production in human endometrial stromal cells and an epithelial cell line (Kniss et al., 1997
; Huang et al., 1998
; Tamura et al., 2002
). In endometriotic cells, the production of MCP-1 is up-regulated by IL-1
(Akoum et al., 1995
). However, no information is available regarding the possible link between the regulation of PG and MCP-1 by IL-1
in human endometrium. Previous studies have indicated that COX metabolites up-regulated MCP-1 in hepatic stellate cells (Efsen et al., 2001
), but repressed MCP-1 formation in experimental glomerulonephritis (Schneider et al., 1999
). These studies infer some cell specificity in the determination of the interaction between PG and MCP-1. It is therefore of interest to study the relationship between PG and MCP-1 in human endometrial cells.
The presence of LH/hCG receptors has been reported for many years in the human endometrium, but their physiological relevance is still questioned (Reshef et al., 1990; Rao, 1999
). hCG, the embryonic signal for the maternal recognition of pregnancy in the human, appears to play an important role in blastocyst implantation (for a review, see Srisuparp et al., 2001
). It is primarily produced by the trophoblast of the placenta. Besides its well-known luteotrophic function, hCG is able to inhibit apoptosis, promote decidualization (Han et al., 1999
) and exert anticarcinogenic and immunomodulatory effects (Russo and Russo, 1994
). Up-regulation of COX-2 gene expression in response to hCG has been demonstrated in both human endometrial stromal and epithelial cells (Han et al., 1996
; Zhou et al., 1999
). In addition, Arici et al. (1997)
reported the induction of higher MCP-1 mRNA expression and protein production by LH/hCG in human ovarian follicles.
Thus, the aims of this study are to investigate the possible relationship between PG and MCP-1 and to study the effect of hCG on IL-1-mediated PG and MCP-1 production. Separated and non-separated human endometrial cell cultures are compared and non-separated human endometrial cells are used in the present study as the primary in vitro model.
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Materials and methods |
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Treatments
The medium was changed every 2 days. After confluence, cells were treated with fresh, serum-free RPMI 1640 medium containing different concentrations of IL-1 (01 ng/ml) (Sigma), IL-1
(1 ng/ml) plus indomethacin (10 µmol/l; Sigma), IL-1
(1 ng/ml) plus NS-398 (10 µmol/l; Cayman, USA), hCG (0.1 µg/ml, 10 000 IU/mg; Sigma), IL-1
(1 ng/ml) plus hCG (0.1 µg/ml), PGE2 (010 µmol/l), PGF2
(010 µmol/l) or MCP-1 (050 ng/ml) in triplicate at 37°C in an atmosphere of 5% CO2:95% air. After 24 h, the culture medium was collected and kept at 20°C for prostaglandin and MCP-1 measurement. Cells were recovered for protein assay.
Immunofluorescence microscopy analysis
Primary separated and non-separated human endometrial cells were grown on Lab Tek 4-well chamber slides (Nalge Nunc International, USA). Cells were fixed with cold methanol for 6 min at room temperature and then rinsed with phosphate-buffered saline (PBS). Slides were then blocked in PBS containing 10% goat serum for 1 h at room temperature. After washing in PBS (three times, 5 min each), slides were incubated with mouse monoclonal antibodies against cytokeratin (recognizing 4, 5, 6, 8, 10, 13 and 18 isoforms) or vimentin (Sigma) at a dilution of 1:200 in PBS containing 0.5% goat serum for 1 h at room temperature. Immunofluorescence was obtained by reaction with a fluorescent secondary antibody (Alexa Fluor® 488 goat anti-mouse IgG; Molecular Probes, Inc., USA) at a dilution of 1:300 in PBS containing 0.5% goat serum for 1 h at room temperature. Slides were then rinsed three times with PBS. Fluorescence was visualized using a Zeiss Axiovert 100-Inverted microscope (Zeiss, Germany) and images captured and integrated using the Northern Exposure program (Empix Imaging Inc., Canada).
Enzyme immunoassays (EIA) for PG
An EIA technique was used for PGE2 and PGF2 measurement as described previously (Asselin et al., 1996
), which utilized acetylcholinesterase-linked PG tracers (Cayman Chemical Company, USA). The inter- and intra-assay coefficients of variation (n=12) were 16 and 10% respectively.
MCP-1 ELISA
MCP-1 in the culture medium was measured using a previously reported sandwich enzyme-linked immunosorbent assay (Akoum et al., 1996). Briefly, 250 ng/well of mouse monoclonal anti-human MCP-1 antibody (R & D systems, USA) and a 1:1000 dilution of rabbit polyclonal anti-human MCP-1 antibody (a generous gift from Dr Paul H.Naccache) were used for detection. TMB (3,3',5,5',-tetramethylbenzidine; Bio-Rad Laboratories Ltd, Canada) was used as the substrate. The enzymatic reaction was stopped by the addition of sulphuric acid. The optical density was determined at 450 nm. MCP-1 concentration was interpolated from the standard curve using recombinant human MCP-1 (R & D systems). The sensitivity for MCP-1 was 50 pg/ml. The intra- and inter-assay coefficients of variation were <6%.
Western blot analysis
Proteins from cultured human non-separated endometrial cells were extracted and quantified as described recently (Chapdelaine et al., 2001). Aliquots of 10 µg protein of each sample were separated on 10% sodium dodecyl sulphatepolyacrylamide gel electrophoresis and then transferred onto nitrocellulose membranes. The membranes were blocked overnight at 4°C in PBS containing 5% fat-free dry milk and 0.05% Tween 20. After 1 h of incubation at room temperature with rabbit anti-sheep COX-1 polyclonal antibody or rabbit anti-sheep COX-2 polyclonal antibody (MerckFroost, Canada) at a dilution of 1:6000 in 1% milk solution, the blots were washed with PBS containing 0.05% Tween 20. A secondary antibody (goat anti-rabbit IgG conjugated with horseradish peroxidase; Jackson Immunoresearch Laboratories, USA) was used for another 1 h at room temperature at a dilution of 1:10 000 in 3% milk solution. Finally, the blots were washed and immunoreactive proteins were visualized with an enhanced chemiluminescent system (Renaissance; NEN, Life Science Products, USA). The density of the signals was determined by computer-assisted densitometry (Biolmage, Visage 110s; Genomic Solutions Inc., USA).
Statistical analysis
Data are presented as the mean±SEM. Statistical analysis was performed using analysis of variance (ANOVA) followed by Fisher's protected least significant difference, Duncan's new multiple range and StudentNewmanKeuls multiple comparison tests (Super ANOVA; Abacus Concepts, USA). The interaction between the effect of IL-1 and cell types and the interaction between hCG and IL-1
were tested using two-way ANOVA. P<0.05 was considered statistically significant.
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Results |
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Epithelial and stromal cells in separated and non-separated cells were identified by cell-specific staining of intermediate filament proteins. Epithelial cells were positively labelled with the epithelium-specific cytokeratin antibody (Figure 1D and F), whereas stromal cells did not react with this antibody. By contrast, stromal cells exhibited a strong vimentin staining (Figure 1E) and epithelial cells weak background staining (data not shown).
Prostaglandin accumulation in the culture medium of human endometrial epithelial, stromal and non-separated cells
PG accumulation in the culture medium of epithelial, stromal and non-separated cells following treatment with IL-1 (1 ng/ml) for 24 h was illustrated in Figure 2. IL-1
significantly increased both PGF2
and PGE2 in stromal cells. In epithelial cells, IL-1
induced a significant up-regulation of PGF2
, but not PGE2. Basal PG levels were comparable in stromal and epithelial cells. However, the effect of IL-1
in stromal cells was significantly higher than in epithelial cells for both PGF2
and PGE2. In non-separated cells, IL-1
stimulated significantly PGE2 and PGF2
(P<0.05).
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Both PGE2 and PGF2 levels were increased in a concentration-dependent manner by IL-1
(Figure 3C). Co-treatment of cells with indomethacin (10 µmol/l), a non-specific COX inhibitor, or NS-398 (10 µmol/l), a COX-2 specific inhibitor, significantly reduced IL-1
-induced prostaglandin secretion.
Effects of IL-1 and COX inhibitors on MCP-1 secretion by human endometrial cells
MCP-1 concentration was measured in the culture medium from the same experiments used for determination of PG production. MCP-1 was detectable in the medium of all cultures but in variable levels. IL-1 enhanced MCP-1 production in a concentration-dependent manner (Figure 3D). Co-treatment of COX inhibitors with IL-1
did not have any effect on MCP-1 levels compared with IL-1
alone.
Effect of prostaglandins on MCP-1 level
Non-separated endometrial cells in culture were incubated with different concentrations of PGE2 (010 µmol/l) or PGF2 (010 µmol/l) for 24 h. Table I showed that PGF2
and PGE2 did not have any significant effect on MCP-1 levels (P>0.05).
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Effects of hCG on IL-1-induced MCP-1 production
As illustrated in Figure 5C, no change was observed in either basal or IL-1-induced MCP-1 levels in response to 0.1 µg/ml hCG.
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Discussion |
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The first indication of the induction of PG by IL-1 in human endometrium dates back to 1990 (Mitchell et al., 1990
). In stromal cells, it was shown that IL-1
can elevate both PGE2 and PGF2
levels by increasing COX-2 mRNA and protein levels (Tamura et al., 2002
). This effect involves protein kinase A (PKA), nuclear factor kappa B (NF-KB), and/or the extracellular signal-regulated kinase 1 and 2 (ERK1/2) signalling pathways (Tamura et al., 2002
). In our study, similar induction of PG by IL-1
is observed in non-separated endometrial cells and correlated with a concentration-dependent increase of COX-2 but not COX-1 protein levels (Figure 3). The time-course of COX-2 induction with a significant increase at 2 h shows a much faster expression than reported before in stromal cells (Huang et al., 1998
). The difference may be due to the presence of epithelial cells.
MCP-1 can be released by many reproductive tissues. A variety of growth factors and cytokines such as tumor necrosis factor- (TNF-
), IL-1 and interferon-
(IFN-
) stimulates MCP-1 secretion. In human endometrium, MCP-1 level is the lowest around the time of ovulation when estrogen is high (Arici et al., 1999
). In glandular epithelial cells, MCP-1 mRNA level is higher than in stromal cells, but not regulated (Arici et al., 1995
). No increase in MCP-1 mRNA levels was found in glandular epithelium treated with IL-1 (Arici et al., 1995
). The mechanisms by which MCP-1 gene transcription is regulated are agonist specific. NF-KB pathway has been suggested for the regulation of MCP-1 by mediators such as IL-1, glucocorticoid, lipopolysaccharide (LPS) and TNF-
(King et al., 2001
; Ueda et al., 1997
). Our data show that in human non-separated endometrial cells, IL-1
stimulation of MCP-1 production is concentration-dependent and highly reproducible, regardless of the possible difference in the proportion of epithelial and stromal cells in each confluent culture (Figure 3D). This indicates that the proportion of epithelial and stromal cells was fairly similar between experiments or that interactions between these cell types make them equivalent in terms of MCP-1 production in response to IL-1
. The increase of MCP-1 in response to IL-1
in the endometrium may be correlated with the activated NF-KB observed during menstruation.
Previous studies have shown that PG can modulate other inflammatory mediators including MCP-1. In ovine and bovine corpus luteum (CL), administration of PGF2 induces MCP-1 mRNA expression (Tsai et al., 1997
). PGE2, an important immunomodulator and mediator of inflammation within the uterus, stimulates MCP-1 release from placenta (Denison et al., 1998
). Additionally, COX inhibitors modulate MCP-1 levels in different ways depending on cell types (Kyrkanides et al., 2002
). In human endometrium, high expression of MCP-1 and COX-2 is observed before the initiation of menstruation, coinciding with leukocyte accumulation in the uterus (Jones et al., 1997
). Collectively, this led us to hypothesize that there could be a relationship between PG and MCP-1 in the endometrium. We show that treatment with indomethacin, a non-specific COX inhibitor, or NS-398, a COX-2-specific inhibitor, markedly reduces PG levels stimulated by IL-1
(Figure 3C). COX inhibitors alone, especially indomethacin, also decreased basal PG accumulation in the culture media (data not shown). However, neither indomethacin nor NS-398 has any effect on either IL-1
-induced (Figure 3D) or basal MCP-1 level (data not shown). Comparing our data with those obtained in hepatic stellate cells and glomerular mesangial cells (Schneider et al., 1999
; Efsen et al., 2001
) confirms that the interaction between PG and MCP-1 varies depending on tissues or cell types. We next investigated MCP-1 production in response to direct addition of PG and found that MCP-1 secretion is not sensitive to PGF2
or PGE2 (Table I). Recent studies demonstrated the presence of PGF2
receptor as well as PGE2 receptors in human endometrium (Milne et al., 2001
; Milne and Jabbour, 2003
). Thus, the lack of response is likely due to the inability of PG to modulate MCP-1 level in endometrial cells. Globally, neither COX inhibitors nor direct addition of PG had any effect on MCP-1 level, suggesting that PG do not play a role in the regulation of MCP-1 synthesis in human endometrial cells. Interestingly, the incubation of cells with MCP-1 gave rise to a significant concentration-dependent increase in PGE2, but not PGF2
production (Figure 4). A time-course study was then conducted to test whether MCP-1 could contribute to PG production induced by IL-1
. The results revealed that a significant increase in PG production was already detectable 2 h following exposure of cells to IL-1
(1 ng/ml), while the up-regulation of MCP-1 was evident only after 4 h (data not shown). Moreover, IL-1
stimulates both PGF2
and PGE2 whereas MCP-1 preferentially stimulates PGE2. These observations suggest that PG production in response to IL-1
stimulation is independent of MCP-1.
Despite its important role in implantation (Simon et al., 1994), IL-1
can disrupt blastocyst implantation by inhibiting decidualization of endometrial stromal cells (Kariya et al., 1991
; Frank et al., 1995
). hCG, a heterodimeric glycoprotein hormone required to maintain pregnancy, exerts its effects through LH/hCG receptors by stimulating progesterone secretion from the corpus luteum in the first trimester. Moreover, hCG is suggested to have important roles within the uterus through an effect on cytokine production (Uzumcu et al., 1998
). IL-6 and TNF-
are stimulated by hCG in human endometrial cells (Uzumcu et al., 1998
). We have tested the possibility that hCG could have an effect on IL-1
via modulation of PG and/or MCP-1 production. We found that at the concentration of 0.1 µg/ml, hCG did not have any effect on basal PG secretion (Figure 5B). The co-treatment of hCG (0.1 µg/ml) with IL-1
(1 ng/ml), however, reduced PG production induced by IL-1
. A significant reduction was observed only for PGF2
(P<0.05). The mechanism by which hCG reduced IL-1
-induced PG is unknown. In gonads, LH/CG receptors are coupled to cAMP generation and act through PKA. This would, however, decrease NF-KB and inhibit MCP-1 production, which is not the case here. In primary baboon endometrial epithelial cells and a human endometrial cell line, hCG does not induce cAMP generation, but rather a PKA-independent ERK1/2 cascade that would also decrease MCP-1 formation (Srisuparp et al., 2001
). Therefore, according to the literature, all mechanisms of hCG action that could decrease PG production would also lead to a reduction of MCP-1 (Tamura et al., 2002
). Therefore, further investigation of this particular action must be conducted to elucidate the mechanisms involved. As indicated in previous studies, suppression of PG synthesis is required for successful implantation (Smith and Kelly, 1988
). This finding in our study supports the local role of hCG in the endometrium. hCG may indirectly modulate the receptive endometrium to facilitate the implantation process. In contrast, hCG did not have any effect on either basal or IL-1
-induced MCP-1 level (Figure 5C). Human CG receptors have been well characterized on human endometrial epithelial and stromal cells (Reshef et al., 1990
). The failure of hCG to suppress IL-1
-induced MCP-1 is surprising because hCG can inhibit various cellular responses mediated by NF-KB. Inhibition of NF-KB activation by hCG is not cell type specific (Manna et al., 2000
). Given the range of hCG concentrations tested (from 0.1 to 10 µg/ml), it seems unlikely that the effective dose was missed. Therefore, MCP-1 levels do not appear to be directly modulated by hCG in human endometrial cells.
In conclusion, IL-1 stimulates the production of both PG and MCP-1 in non-separated human endometrial cells by apparently distinct and independent mechanisms. hCG, added in combination with IL-1
, is able to block the induction of PG synthesis but not that of MCP-1. These results support the role for cytokines in the regulation of endometrial cell function and of a local action of hCG in the uterus.
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Acknowledgements |
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Submitted on June 23, 2003; resubmitted on March 19, 2004; accepted on July 20, 2004.