Molecular Human Reproduction, Vol. 10, No. 2, pp. 109-113, 2004
© European Society of Human Reproduction and Embryology 2004
Mechanical stretch activates type 2 cyclooxygenase via activator protein-1 transcription factor in human myometrial cells
1Imperial College Parturition Research Group, Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH and 2Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, DuCane Road, London W12 0NN, UK
3 To whom correspondence should be addressed. e-mail: mark.johnson{at}imperial.ac.uk
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ABSTRACT |
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The uterus is subject to stretch throughout pregnancy, which, in the presence of progesterone, is a potent stimulus for uterine growth. However, in the absence of progesterone or when stretch is excessive, as in multiple pregnancy, it may provoke the onset of labour. We have investigated the effect of stretch on prostaglandin synthesis in primary human uterine myocytes [non-pregnant (NP), pregnant not in labour (NL) and pregnant in labour (L)]. The cells were grown on flexible bottom culture plates and subjected to 1 or 6 h static stretch. Expression of type 2 cyclooxygenase (COX-2) mRNA was similar in samples obtained from NP and L groups and both were significantly greater than those found in the NL group. Stretch of cells from all groups resulted in increased COX-2 mRNA expression. In further studies carried out on cells taken from the NL group, 6 h of stretch resulted in increased COX-2 protein levels and, in the media, increases in prostaglandin (PG) I2 metabolite and PGE2 concentrations and a reduction in the concentration of PGF2
metabolites. After stretch, EMSA studies showed increased activator protein-1 (AP-1) nuclear protein DNA binding activity but not of nuclear factor 
B. These data demonstrate that stretch of human myocytes results in increased COX-2 activity and suggest that this may occur through activation of the AP-1 system. Key words: Key words: cyclooxygenase-2/labour/myometrium/pregnancy/stretch
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Introduction |
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During normal pregnancy, the uterus increases several-fold in size by a combination of hyperplasia and hypertrophy. In a progesterone-dominated endocrine environment, moderate stretch probably initiates and maintains this process; however, in the absence of progesterone or if stretch is excessive, the response of the uterus is to contract. Clinically this is important in multiple pregnancy, where the excessive stretch is responsible for the onset of labour which is preterm in >50% of twin and >80% of triplet pregnancies. Studies in the sheep, rat and wallaby have shown that stretch increases the mRNA for oxytocin receptor (Ou et al., 1998; Wu et al., 1999; Parry and Bathgate, 2000), type 2 cyclooxygenase (COX-2; Wu et al., 1999) and connexin43 (Ou et al., 1997). Thus, stretch-induced labour probably occurs through the increased expression of contraction-associated proteins.
Increased prostaglandin synthesis is thought to play a key role in the onset and progress of labour. Myometrial COX-2 mRNA expression and activity has been shown to increase at term and with the onset of labour (Slater et al., 1998; Mesiano et al., 2002). Stretch of the sheep uterus is associated with increased COX-2 mRNA expression (Wu et al., 1999) and in the human, uterine stretch, achieved by inflating a balloon placed in the uterine cavity in postpartum women, is also associated with increased prostaglandin synthesis (Manabe et al., 1983). The mechanism involved in the up-regulation of COX-2 activity at the time of labour or by stretch is uncertain, but several stimuli, including interleukin-1ß (IL-ß1), increase COX-2 expression. In the amnion, IL-ß1 increases COX-2 expression via the transcription factor nuclear factor B (NFB) (Allport et al., 2001). The COX-2 promoter also contains binding sites for activator protein-1 (AP-1) which is formed by dimers of cFos and cJun. The expression of c-fos is increased prior to the onset of labour in the rat (Mitchell and Lye, 2002) and mechanical stretch of rat uterine myocytes is associated with c-fos induction (Shynlova et al., 2002).
Stretch may be constant, as might be expected during pregnancy, or episodic, as at the time of labour. In our studies, we are investigating the role of stretch during pregnancy and consequently have used constant and not episodic stretch. In this study, using primary cultures of human myometrial cells, we have tested the hypothesis that stretch increases COX-2 activity, mediated through increased AP-1 and/or NFB activity.
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Materials and methods |
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Tissue specimens
Biopsies (0.5x0.5x0.5 cm3) of term human myometrium were collected from the upper margin of the incision made in the lower segment of the uterus at the time of caesarean section from women not in labour (NL, n = 6), during active labour (L, n = 6) and at the time of hysterectomy [non-pregnant (NP), n = 6 ] into DMEM medium containing 100 mIU/ml penicillin and 100 µg/ml streptomycin. Samples were stored at 4°C for
3 h prior to cell preparation for culture. Median (range) maternal ages were: NL = 31 (26–37) years; L = 30 (27–40) years. Median (range) patient age at hysterectomy was 42 (39–47). In the pregnant samples, median (range) gestational age [NL = 39 (38 + 3 – 39 + 2) and L = 38 + 5 (37 – 40 + 4) weeks] did not differ significantly. The indications for Caesarean section in the active labour group were: slow labour, fetal distress and breech presentation, and in the non-labour group, previous Caesarean section (LSCS), breech presentation and maternal request. All specimens were obtained after informed consent. The Riverside Research Ethics Committee approved the study.
Cell culture
Primary human uterine myocytes were isolated using a mixture of collagenases and cultured in Dulbecco’s modified Eagle’s medium (DMEM) medium containing 7.5% fetal calf serum, 100 mIU/ml penicillin and 100 µg/ml streptomycin in T75 in an atmosphere of 5% CO2:95% air at 37°C (Pieber et al., 2001). Myometrial cells in this preparation have previously been characterized (Pieber et al., 2001). Cells from passage 1 to 4 were trypsinized in 0.25% trypsin containing 0.02% EDTA in PBS and cultured in 6-well flexible-bottomed culture plates pre-coated with collagen type I in 3 ml of DMEM medium. When cells were 85–95% confluent (day 3–4), medium was removed and replaced with 3 ml of fresh medium supplemented with 7.5 mmol/l HEPES with 1% FCS. After 16 h these were subjected to a static stretch of 6, 11 and 16% for 1 or 6 h using a Flexercell strain unit (Flexcell International Corp., USA). Unstretched cells grown and treated similarly were aliquoted and used as controls. At the end of the specified time (1 or 6 h), medium was removed, aliquoted and frozen at –80°C. More than 99% of cells remained attached to the 6-well culture plates after stretch protocols and these cells were frozen in liquid nitrogen for extraction of RNA or precipitated with protein extraction buffer for cytosolic protein and nuclear protein extracts.
Quantitative RT–PCR
Total RNA was extracted and purified from myometrial cells grown in 6-well flexible-bottomed culture plates using RNeasy mini kit (Qiagen Ltd, UK). After quantification, 1.0 µg was reverse-transcribed with oligo dT random primers using MuLV reverse transcriptase (Applied Biosystems Ltd, UK). Primer sets for COX-2, OTR and glyceraldehyde-6-phosphate dehydrogenase (GAPDH) were designed and obtained from (Amersham Pharmacia Biotech). OTR sense 5'-GCCTTATCAGCTTCAAGATCTTGG-3', antisense 5'-CAGGACAAAGGAGGACGAGTTGC-3'; COX-2 sense 5'-TTC AAATGAGATTGTGGGAAAATTGCT-3', antisense 5'-AGATCATCTCTG CCTGAGTATCTT-3'; GAPDH sense 5'-TGATGACATCAAGAAGGT GGTGAAG-3', antisense 5'-TCCTTGGAGGCCATGTGGGCCAT-3'. These primer sets produced amplicons of the expected size and flanked intron/exon junctions. Assays were validated for all primer sets by confirming that single amplicons of appropriate size and sequence were generated according to predictions. Quantitative PCR was performed in the presence of SYBR Green (Roche Diagnostics Ltd, UK), and amplicon yield was monitored during cycling in a LightCycler Sequence Detector (Roche Diagnostics) that continually measures fluorescence caused by the binding of the dye to double-stranded DNA. Pre-PCR cycle was 7 min at 95°C followed by 35 cycles of 95°C for 10 s, 56–60°C for 10 s and 72°C for 10 s followed by final extension 72°C for 1 min. The cycle at which the fluorescence reached a preset threshold (cycle threshold) was used for quantitative analyses. The cycle threshold in each assay was set at a level where the exponential increase in amplicon abundance was approximately parallel between all samples. All mRNA abundance data were expressed relative to the amount of the constitutively expressed GAPDH.
Conventional PCR was performed using Ampli-Taq Gold DNA polymerase (Applied Biosystems Ltd). Pre-PCR cycle was 10 min at 95°C followed by 35 cycles of 95°C for 1 min, 56–60°C for 1 min and 72°C for 1 min followed by final extension 72°C for 10 min.
Western blot analysis
Protein extracts were prepared from myometrial samples by homogenization in 10 vol T-Wash (50 mmol/l Tris buffer, 10 mmol/l EDTA, 1% Triton-100, with 10 mmol/l phenylmethylsulphonyl fluoride, 4 µg/ml pepstatin and 0.5 µg/ml leupeptin) for 30 s. The supernatant was separated from tissue debris by centrifugation at 1000 g for 10 min at 4°C. Protein concentrations were determined by Protein assay (Bio-Rad Laboratories, USA) and bovine serum albumin (BSA) reference standards. Electrophoresis was carried out on 20 µg aliquots of protein samples, in 2xloading buffer [4% sodium dodecyl sulphate (SDS), 20% glycerol, 10% 2-mercaptoethanol, 0.004% Bromophenol Blue, and 0.125 mol/l Tris–HCl, pH 6.8]. Samples were boiled for 5 min, quenched on ice and subsequently run on a 10% SDS–polyacrylamide gel.
Western blotting was carried out following electrophoretic transfer, in 25 mmol/l Tris, 192 mmol/l glycine and 20% v/v methanol, pH 8.3, onto Hybond ECL nitrocellulose membrane (Amersham Life Science, UK). Membranes were blocked in 5% Marvel–0.1% Tween–phosphate-buffered saline (PBS), for 1 h at room temperature. Affinity-purified goat polyclonal antibodies, directed against the peptide immunogen, were used for COX-2 (COX-2 No. sc-1745: Santa Cruz Biotechnology, USA) at a dilution of 1:500, and incubated overnight at 4°C. Membranes were washed in 0.1% Tween–PBS and then incubated with anti-goat immunoglobulin G–horseradish peroxidase (IgG–HRP) secondary antibody at a dilution of 1:2000 for 1 h at room temperature. ECL Western blotting detection was carried out using standard protocols (Amersham Life Science). Protein band size was determined using Rainbow coloured protein molecular weight markers (Amersham Life Science). IL-1ß-stimulated human lymphocytes were used as a positive control for COX-2.
Electrophoretic mobility shift assays (EMSA)
The gel shift was carried out by incubating nuclear protein extracts from unstretched and stretched myocytes cultured under different conditions with a 32P-end-labelled oligonucleotide containing NFB or AP-1 consensus sequence. Nuclear protein (10–20 µg) was used in binding reactions as described previously (Dignam et al., 1983) with the consensus NFB binding site as the probe (Promega). Specificity was determined by competition with 100-fold excess of non-radiolabelled probe. Supershift analysis was performed by the addition of antisera to p65, p50, p52, RelB and cRel (Santa Cruz, USA) on ice 90 min prior to addition of labelled probe. Electrophoresis was performed on a 6% non-denaturing acrylamide gel in 0.25xTris–borate–EDTA (TBE). Gels were dried and protein–DNA complexes were visualized by autoradiography. The reaction products are then analysed on a non-denaturing polyacrylamide gel.
ELISA
The concentration of prostaglandins E2 and F2a and of the prostacyclin metabolite 6-keto-PGF1a, in medium collected from unstretched and stretched cells, were measured using ELISA kits purchased from R & D Systems Ltd.
Statistical analysis
Differences between COX-2:GAPDH mRNA ratios from unstretched and stretched cells were assessed by Wilcoxon signed ranks test (non-parametric test for related samples) using SPSS 10.0. Kolmogorov–Smirnov and Shapiro–Wilk statistics were used to determine normality of each sample pair. Differences were considered statistically significant at P < 0.05.
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Results |
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The concentrations of COX-2 mRNA in samples obtained from NP and L groups were similar and significantly greater than those found in the NL group (P < 0.05, Figure 1A). One hour stretch (6–16%) of cells from all groups resulted in increased COX-2 mRNA expression (Figure 1B–D). In further studies carried out on cells taken from the NL group, 6 h of stretch resulted in increases in PGI2 metabolites and PGE2 concentration and a reduction in the concentration of PGF2
metabolites in the media (Figure 2A–C; P < 0.05) and increases in COX-2 protein levels (Figure 3). Specific binding of nuclear protein to AP-1 consensus sequence was increased by 6 h of stretch (Figure 4). NFB was not increased by 6 h of stretch (Figure 5).
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Discussion |
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Our data show that COX-2 expression in human uterine myocytes is reduced during pregnancy but increases with the onset of labour. Furthermore, 1 h stretch increases uterine myocyte COX-2 mRNA expression independent of reproductive state and in association with activation of the AP-1. Our subsequent experiments used 6 h stretch to allow sufficient time for increased mRNA to be translated into protein and for increased prostaglandin synthesis to take place and showed that stretch results in increased COX-2 protein synthesis and activity.
Our finding of a relatively higher increased COX-2 mRNA expression in non-pregnant compared to pregnant samples implies that myometrial COX-2 expression is reduced during pregnancy. This would be consistent with a predominant progesterone influence at this time since we have shown progesterone to inhibit IL-1ß-stimulated expression of COX-2 mRNA in amnion epithelial cells (Loudon et al., 2003). The greater levels of COX-2 mRNA in myocytes obtained from labouring women when compared to those obtained from women at term but not in labour are consistent with a previous report of PR expression in whole myometrial tissues (Mesiano et al., 2002). In our own earlier study (Slater et al., 1998), we showed that COX-2 expression in myometrium increases at term but not further with the onset of labour. That study, however, used a less robust method for quantification of mRNA whereas the more recent studies have used more reliable real time RT–PCR methods. COX-2 mRNA expression has been reported to be elevated in the sheep myometrium with the onset of betamethasone-induced labour (Wu et al., 1999), and that the increase was greater in the gravid horn than in the non-gravid horn. This led the authors to suggest that the difference was related to mechanical stretch of the gravid horn. Surprisingly, although various investigators in several animals have studied the effect of stretch upon a range of labour-associated proteins, there are no other studies of the effect of stretch upon COX-2 expression. In human clinical studies performed prior to the discovery of COX-2, Manabe et al. (1983) found that mechanical stretch of the uterus increased contractility and prostaglandin synthesis, and that indomethacin partially inhibited the stretch-induced contractions. Our data show that stretch increased COX-2 mRNA expression independent of reproductive state and that this increase was associated with increased COX-2 protein synthesis and activity. Whether the increase in COX-2 with the onset of labour is initiated by increasing myometrial stretch alone or by the combination of stretch and functional progesterone withdrawal is uncertain. However, recent data show that prostaglandins can increase PR-A expression, suggesting that the primary step may be an increase in COX-2 activity leading to an alteration in the PR-A:PR-B ratio (Madsen et al., 2003).
We have found that stretch increases the synthesis of prostaglandin E2 and prostacyclin (measured as its stable metabolite 15-keto PGF1) but decreases prostaglandin F2 synthesis. Synthesis of both prostaglandin E2 and prostacyclin requires the action of a specific synthase, downstream of COX. Prostaglandin F2 may be produced either enzymatically or non-enzymatically from the prostaglandin endoperoxides. It is possible that stretch either increases the activity of COX but differentially affects the subsequent synthases, as has been shown previously (Itoh et al., 2002), or that decreased prostaglandin F2 synthesis is due to shunting of prostaglandin endoperoxides through the prostaglandin E2 and prostacyclin synthase pathways. Prostacyclin is principally a myometrial relaxant, whilst prostaglandin E2 causes relaxation when acting at EP2 and EP4 receptors and contractions when acting at EP1 and EP3 receptors. Smith et al. (2001) found higher expression of EP1 and EP3 and lower expression of EP2 in the fundus compared to the lower segment of the baboon uterus and an overall decrease in EP2 with the onset of labour. Brodt-Eppley and Myatt (1999) found a reduction in both FP and EP2 expression with advancing gestation but increased FP expression with the onset of labour. Therefore, whether stretch of the human myometrium leads to contractions or relaxation will be determined by the pattern of prostaglandin receptor expression. The effect of stretch upon prostaglandin receptor expression will also be an important factor. Although Ou et al. (2000) have shown that stretch does not increase rat myometrial FP expression, there are currently no animal or human data relating to EP expression in response to stretch.
Previously, we have reported that NFB mediates both IL-1ß-stimulated and labour-associated COX-2 mRNA expression in amnion (Allport et al., 2001). Furthermore, Belt et al. (1999) have shown that NFB mediates IL-1ß-stimulated COX-2 expression in myometrium. In several cell types—fibroblasts, osteoblasts and pulmonary artery smooth muscle cells—stretch activates NFB (Chaqour et al., 1999; Granet et al., 2001; Inoh et al., 2002), however, our data suggest that stretch does not activate NFB in human uterine myocytes. We found that stretch activated the AP-1 transcription system—in the rat, both labour and stretch—leading to increased expression of AP-1-related transcription factors (Mitchell and Lye, 2002; Oldenhof et al., 2002). To prove that AP-1 activation is responsible for the up-regulation of COX-2 expression, we attempted to transfect a construct of the COX-2 promoter linked to luciferase reporter into myocytes and had planned to assess the effect of stretch and of site-directed mutation of the AP-1 binding sites. However, although we have been able to reliably transfect myocytes with other DNA constructs, and to reliably transfect other cell types (e.g. amnion cells and fibroblasts) with COX-2 promoter constructs, we could not, despite using a wide variety of protocols, reliably transfect myocytes with the COX-2 promoter constructs which we have available.
Our data suggest that stretch of human myometrial cells leads to increased prostaglandin synthesis via COX-2 activity and mediated through increased binding at the AP-1 promoter site. The pattern of myometrial prostaglandin synthesis following stretch would probably result in myometrial relaxation. However, since PGE2 may act either to stimulate or inhibit myometrial contractility, the effect of stretch will be determined by the prevailing pattern of prostaglandin receptor expression.
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Acknowledgement |
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This work was supported by a grant from Wellbeing.
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Submitted on October 28, 2003; accepted on November 10, 2003.
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