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Mol. Hum. Reprod. Advance Access originally published online on August 25, 2006
Molecular Human Reproduction 2006 12(10):625-631; doi:10.1093/molehr/gal061
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Myometrial prostaglandin E2 synthetic enzyme mRNA expression: spatial and temporal variations with pregnancy and labour

S.R. Sooranna1, P.L. Grigsby2, N. Engineer1, Z. Liang1,3, K. Sun2, L. Myatt2 and M.R. Johnson1,4

1Imperial College Parturition Research Group, Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster Hospital, London, UK, 2Department of Obstetrics & Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH, USA and 3Department of Obstetrics & Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China

4 To whom correspondence should be addressed at: Imperial College Parturition Research Group, Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. E-mail: mark.johnson{at}imperial.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
We have investigated the hypothesis that the expression of the enzymes involved in PGE2 synthesis in the human uterus is co-ordinated. We have studied (i) the mRNA expression of the enzymes involved in PGE2 synthesis [phospholipases (cPLA2 and sPLA2), prostaglandin H synthase (PGHS)-2 and PG E synthases (PGES-1 and -2)] and their relationship to the expression of inflammatory cytokines in samples of myometrium obtained from pregnant women undergoing caesarean section (LSCS) either before or after the onset of labour at or before term; and (ii) the effect of IL-1ß, IL-6, TNF-{alpha}, PGE2 and stretch on PGE2 enzyme mRNA expression. We found that cPLA2, sPLA2 and PGHS-2 mRNA expression were greater in labour samples; cPLA2, sPLA2, PGHS-2, PGES-1 and -2 mRNA expression were greater in lower- than upper-segment samples; and there was no effect of gestational age. PGHS-2 mRNA levels correlated with those of PGES-1, cPLA2, IL-1ß and IL-8; PGES-1 mRNA levels correlated with those of IL-1ß, IL-8 and cPLA2. In primary cultures of uterine myocytes, cPLA2 mRNA expression was increased by IL-1ß and IL-6; PGHS-2 mRNA expression was increased by IL-1ß, PGE2 and stretch; and PGES-1 mRNA expression was increased by IL-1ß only. These data show that labour is associated with increased expression of the enzymes involved in PGE2 synthesis and their expression is greater in the lower uterine segment. The presence of associations between the levels of PGE2 enzyme mRNA expression and the effects of IL-1ß suggest that their expression is co-ordinated and that IL-1ß is the responsible factor.

Key words: cytokines/labour/prostaglandin synthesis/stretch/uterine smooth muscle cells


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Many studies have confirmed the important role played by prostaglandins (PG) during human labour, which promote both cervical compliance and myometrial contractility. Most studies have suggested that in the process of PG synthesis at the time of labour, PG H synthase (PGHS) type 2 plays the most important role (Hirst et al., 1995bGo; Slater et al., 1995Go, 1999Go). However, several other enzymes are involved in PGE2 synthesis and there are relatively little data available in terms of the spatial and temporal variations and the effect of labour on their expression and what factors may be important in their regulation.

PG synthesis involves the mobilization of the precursor arachidonic acid from membrane phospholipids, which is then converted to the PG intermediate PGH2 by PG H synthase (PGHS). Specific PG synthase enzymes convert PGH2 to the different families of PGs. The release of arachidonic acid from intracellular membrane phospholipids is catalysed by the action of phospholipase A2 (PLA2). These enzymes have been broadly divided into two classes, the secretory and cytosolic phospholipases (sPLA2 and cPLA2, respectively). sPLA2 type-IIA and cPLA2 type-IV have been identified within the human uterus (Skannal et al., 1997Go; Lappas et al., 2004Go) and the expression of sPLA2, but not cPLA2, has been found to increase in human myometrium with the onset of labour (Slater et al., 2004Go). Two isoforms of PGHS exist in most cells and are encoded for by two distinct genes—the constitutively expressed PGHS-1 and the inducible PGHS-2 (Hla and Neilson, 1992Go), but only the latter increases in association with labour in fetal membranes and myometrium (Hirst et al., 1995aGo; Slater et al., 1999Go; Challis et al., 2000Go; Lindstrom and Bennett, 2004Go). PGE synthases (PGES), cytosolic PGES (cPGES or PGES-1) and membrane-bound PGES (mPGES or PGES-2) are responsible for PGE2 synthesis (Jakobsson et al., 1999Go; Watanabe et al., 1999Go). Recent studies in humans have localized mPGES to fetal membranes (Meadows et al., 2003Go) and myometrial cells with no significant changes in the latter with gestational age or the onset of preterm or term labour (Giannoulias et al., 2002Go). Thus, several enzymes are involved in the synthesis of PGE2, their expression may be co-ordinated and inflammatory cytokines are prime candidates. IL-1ß is known to increase the expression and activity of PGHS-2 in human myometrial cells (Sooranna et al., 2005Go), but whether IL-1ß or other inflammatory cytokines affect the expression of the other components of the PGE synthetic pathway in myometrium is not known.

In this study, to test the hypothesis that the expression of the enzymes involved in PGE2 synthesis is co-ordinated, we have investigated the spatial and temporal variation in the mRNA expression of the enzymes involved in PGE2 synthesis, cPLA2, sPLA2, PGHS-2 and PGES-1 and -2 in the human uterus; their inter-relationships and relationship to the expression of inflammatory cytokine (IL-1ß and IL-8); and in primary cultures of human uterine smooth muscle cells, we have studied the effect of IL-1ß, IL-6, TNF-{alpha}, PGE2 and stretch on their mRNA expression.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Myometrial samples, collection and preparation
Paired upper and lower human myometrium were obtained from four groups of women (n = 6, in each group) at the time of caesarean section (LSCS) under the conditions of preterm with labour (PTL; 33.9 ± 1.5 weeks), preterm no labour (PTNL; 30.4 ± 1.5 weeks), term with labour (TL; 39.2 ± 0.5 weeks) or term no labour (TNL; 38.4 ± 0.4 weeks). Labour was defined as the presence of regular uterine contractions (every 3–4 min) resulting in cervical effacement and dilation. Myometrial samples were removed from the upper margin of the incision made in the lower uterine segment (lower), while the upper segment was removed from just below the fundus. The indications for LSCS included fetal distress, previous LSCS, failure to progress and breech presentation. All tissue samples were immediately frozen in liquid nitrogen and stored at –80°C. Tissues were collected after patient consent and according to the guidelines set forth in the protocol that is in compliance with the Institution Review Board of the University of Cincinnati (Cincinnati, OH, USA).

Primary myocyte cultures
Biopsies (0.5 x 0.5 cm3) of term human myometrium were collected from at the time of LSCS from women not in labour (n = 6) into Dulbecco’s modified Eagle’s medium (DMEM) containing 100 munits/ml penicillin and 100 µg/ml streptomycin. Samples were stored at 4°C for no >3 h prior to cell preparation for culture. Tissue from LSCS was removed from the upper margin of the incision made in the lower segment of the uterus; mean gestational age was 39 weeks (38 + 3 – 39 + 2). The indications for LSCS included previous LSCS, breech presentation and maternal request. All specimens were obtained after patient consent, and the Riverside Research Ethics Committee approved the study.

Primary human myometrial cells were isolated using a mixture of collagenases and cultured in DMEM, 7.5% fetal calf serum, 100 munits/ml penicillin and 100 µg/ml streptomycin in T75 flasks in an atmosphere of 5% CO2 : 95% air at 37°C (Sooranna et al., 2004Go). Myometrial cells grown in this manner have previously been characterized (Slater et al., 1999Go). For stretch protocols, cells from passage 1–4 were trypsinized in 0.25% trypsin containing 0.02% EDTA in phosphate-buffered saline (PBS) and cultured in 6-well flexible-bottomed culture plates pre-coated with collagen type I in 3 mL of DMEM. When cells were 85–95% confluent (day 3–4), old medium was removed and replaced with 3 mL of fresh medium supplemented with 7.5 mM HEPES and reduced fetal calf serum (FCS) (1%) overnight. After 16 h, the cells were then subjected to a static stretch of 11% for 1 h using a flexercell strain unit (Flexcell International, McKeesport, PA, USA). Unstretched cells were grown, treated similarly and used as controls. More than 99% of cells remained attached to the 6-well culture plates after stretch protocols, and these cells were frozen in liquid nitrogen and stored at –80°C for extraction of RNA.

For incubations with cytokines and PGE2, cells from passage 1–4 were treated as described above and cultured in 6-well plates (Nunc A/S, Rosklide, Denmark) pre-coated with collagen type I in 3 mL of DMEM. When cells were 85–95% confluent, old medium was removed and replaced with 3 mL of fresh medium supplemented with 7.5 mM HEPES but only 1% FCS overnight. After 16 h, cells were incubated with 1 ng/ml TNF-{alpha}, 1 ng/ml IL-1ß, 1 ng/ml IL-6 or 0.1 nM PGE2 (all reagents were obtained from Sigma Chemical Company, Poole, Dorset, UK). After 24 h, medium was removed and cells were frozen in liquid nitrogen and stored at –80°C for extraction of RNA.

Quantitative RT-PCR
Total RNA was extracted and purified from the upper- and lower-segment myometrial samples using the Tri-reagent method (Trizol®, Sigma Chemical Company). After quantification, 2.0 µg RNA was pre-treated with DNase I (Amp Grade, Invitrogen, Paisley, UK) and then samples were reverse transcribed with Oligo dT random primers using SuperScriptTM II reverse transcriptase (Invitrogen). Total RNA was extracted and purified from myometrial cells grown in 6-well flexible-bottomed culture plates using RNeasy mini-kit from Qiagen, Crawley, West Sussex, UK. After quantification, 1.0 µg was reverse transcribed with oligo dT random primers using MuLV reverse transcriptase (Applied Biosystems, Warrington, Cheshire, UK).

Paired oligonucleotide primers for amplification of PGE2 synthetic enzymes were designed using Primer Designer (Scientific and Educational Software, Durham, NC, USA) against the sequence downloaded from GenBank. The primer sets used (Table I) produced amplicons of the expected size and where feasible flanked intron–exon junctions. Assays were validated for all primer sets by confirming that single amplicons of appropriate size and sequence were generated. Quantitative PCR was performed in the presence of SYBR Green (Qiagen), and amplicon yield was monitored during cycling in a RotorGene Sequence Detector (Corbett Research, Mortlake, Sydney, Australia) that continually measures fluorescence caused by the binding of the dye to double-stranded DNA. Pre-PCR cycle was 10 min at 95°C followed by up to 45 cycles of 95°C for 20 s, 58–60°C for 20 s and 72°C for 20 s followed by an extension at 72°C for 15 s. The final procedure involves a melt over the temperature range of 72–99°C rising by 1° steps with a wait for 15 s on the first step followed by a wait of 5 s for each subsequent step. The cycle threshold in each assay was set at a level where the exponential increase in amplicon abundance was approximately parallel between all samples. mRNA data were expressed relative to the amount of the constitutively expressed housekeeping genes beta actin and glyceraldehyde-3-phosphatedehydrogenase (GAPDH) for myometrial tissue samples and primary myometrial cell cultures, respectively. Different housekeeping genes were used as we have found that in primary uterine myocytes cell culture, GAPDH showed less variation and that in myometrial samples, beta actin showed less variation (Sooranna et al., unpublished observation).


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  		Table 1. The primer pairs, gene bank accession numbers and nucleotide sequence numbers for the primers pairs used

 

Statistical analysis
The data were not normally distributed and were therefore expressed as median and range. Analysis was performed with Mann–Whitney test for unpaired samples and Wilcoxon matched pairs test for paired samples, as appropriate, using InStat 3 for MacIntosh, GraphPad, San Diego, CA, USA. Differences were considered statistically significant at P < 0.05. Pearson correlation coefficients were calculated using Prism 4 for MacIntosh, GraphPad.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Expression of PGE synthetic enzyme mRNA in myometrium
For cPLA2, overall, levels were higher in labour (L) versus non-labour (NL, P < 0.01) and in lower segment (LS) versus upper segment (US, P < 0.05) samples and not different between preterm (PT) versus term (T) samples; differences between NL and L samples defined by region and gestational group are shown in Figure 1a. For sPLA2 overall, levels were higher in L versus NL (P < 0.001) and in LS versus US (P < 0.0001) samples and not different between PT versus T samples; differences between NL and L samples defined by region and gestational group are shown in Figure 1b. For PGHS-2, overall, levels were higher in L versus NL (P < 0.0001) and in LS versus US (P < 0.01) samples and not different between PT versus T samples; differences between NL and L samples defined by region and gestational group are shown in Figure 1c. For PGES-1, overall, levels were higher in LS versus US (P < 0.0001), and not different between L versus NL and PT versus T samples; differences between NL and L samples defined by region and gestational group are shown in Figure 1d. For PGES-2, overall, levels were higher in LS versus US (P < 0.05) samples and not different between L versus NL and PT versus T samples; differences between NL and L samples defined by region and gestational group are shown in Figure 1e. The cytokine (IL-1ß and IL-8) data are not shown.


Figure 1
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  		Figure 1. (a) Log cPLA2, (b) sPLA2, (c) log PGHS-2, (d) log PGES-1 and (e) PGES-2 : beta actin mRNA ratio (median, interquartile range and range) in paired upper and lower human myometrial samples obtained from four groups of women (n = 6, in each group), at the time of caesarean section (LSCS) under the conditions of preterm with labour (PTL; 33.9 ± 1.5 weeks), preterm no labour (PTNL; 30.4 ± 1.5 weeks), term with labour (TL; 39.2 ± 0.5 weeks) or term no labour (TNL; 38.4 ± 0.4 weeks). *P < 0.05, **P < 0.01 and ***P < 0.001. NS, not significant.

 

Correlations with myometrial PGE synthetic enzyme mRNA
Correlations were found between cPLA2 and both PGHS-2 (r = 0.65, P < 0.0001) and PGES-1 (r = 0.55, P < 0.0003, Table II); PGHS-2 and PGES-1 (r = 0.86, P < 0.0001, Figure 2a), IL-1ß (r = 0.48, P < 0.0005) and IL-8 (r = 0.31, P < 0.03, Table II); PGES-1 and IL-1ß (r = 0.82, P < 0.0001, Figure 2b) and IL-8 (r = 0.6, P < 0.0001, Table II).


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  		Table II. The associations of the PGE2 synthetic enzyme mRNA levels with each other and with those of the cytokines IL-1ß and IL-8, correlation coefficient (r, 95% confidence limits, P value)

 

Figure 2
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  		Figure 2. The relationship (a) between log PGES-1 and log PGHS-2 [r = 0.86 (0.77–0.92), p < 0.0001) and (b) between log IL-1ß and log PGES-1 [r = 0.82 (0.7–0.89), P < 0.0001] in myometrial samples obtained from women before and after the onset of labour before and at term as shown by the symbols, closed circles, term labour; open circles, term no labour; closed triangles, preterm labour; open triangles, preterm no labour.

 

Effect of IL-1ß, IL-6, TNF-{alpha}, PGE2 and stretch on PGE synthetic enzyme mRNA expression
cPLA2 mRNA expression was increased by IL-1ß (P < 0.01) and IL-6 (P < 0.05, Figure 3a); sPLA2 mRNA expression was unaffected by any treatment (Figure 3b); PGHS-2 mRNA expression was increased by IL-1ß (P < 0.01), PGE2 (P < 0.05) and stretch (P < 0.05, Figure 3c); PGES-1 mRNA expression was increased by IL-1ß only (P < 0.01, Figure 3d); and PGES-2 mRNA expression was unaffected by any treatment (Figure 3e).


Figure 3
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  		Figure 3. Percentage change in (a) cPLA2, (b) log sPLA2, (c) log PGHS-2, (d) log PGES-1 and (e) and PGES-2 : GAPDH mRNA ratio (median, interquartile range and range) in primary cultures of uterine smooth muscle cells exposed to TNF-{alpha} (1 ng/ml), IL-1ß (1 ng/ml), IL-6 (1 ng/ml), PGE2 (1 nmol/l) all for 24 h and 11% stretch for 6 h. *P < 0.05 and **P < 0.01.

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
These data show that labour is associated with increased expression of cPLA2, sPLA2 and PGHS-2 mRNA and that the lower segment expresses higher mRNA levels of key enzymes involved in PGE2 synthesis. Further, we found associations between PGE2 synthetic enzyme mRNA levels and those of inflammatory cytokines and increments in the key PGE2 synthetic enzyme mRNA expression in response to IL-1ß. Overall, these data suggest that the expression of the enzymes involved in PGE2 synthesis is co-ordinated and that the prime candidate for this effect is IL-1ß.

Myometrial cPLA2 mRNA expression and/or enzyme activity were unchanged with the onset of labour in the sheep and mouse (Zhang et al., 1996Go; Wu et al., 1998Go; Winchester et al., 2002Go), but increased in the guinea pig cervix (Rajabi and Cybulsky, 1995Go). Studies in human myometium report a non-significant increase in cPLA2 protein levels with advancing gestation (Korita et al., 2002Go) and an increase in myometrial sPLA2, but not cPLA2, mRNA expression with the onset of labour (Slater et al., 2004Go). These results are consistent with our sPLA2, but not our cPLA2, data. However, given that we found relationships between cPLA2 and both PGHS-2 and PGES-1 and none for sPLA2 and that cPLA2, but again not sPLA2, mRNA expression was increased by IL-1ß and IL-6, it seems that it is likely that cPLA2 is a part of the co-ordinated up-regulation of the PGE2 synthetic enzymes associated with labour. However, although IL-1ß increased cPLA2 mRNA expression, there was no association between myometrial levels of IL-1ß mRNA and those of cPLA2, suggesting in this case that the effect of IL-1ß may not be direct.

The expression of PGHS-2 mRNA in human myometrium is reported to increase with the onset of labour in humans (Hirst et al., 1995aGo; Slater et al., 1999Go; Challis et al., 2000Go; Lindstrom and Bennett, 2004Go). Our data are consistent with this except that the increase in PGHS-2 mRNA in the upper segment with the onset of preterm labour did not reach statistical significance. What is responsible for the increase in PGHS-2 expression with the onset of labour is not clear, but IL-1ß may play an important role. This would be consistent with previous observations (Bartlett et al., 1999Go; Sooranna et al., 2005Go) and the results of this study showing associations between IL-1ß and PGHS-2 (r = 0.48) in myometrial samples and an increase in PGHS-2 mRNA expression in response to IL-1ß. Interestingly, the association between IL-1ß and PGHS-2 (0.48) was weaker than that observed between PGES-1 and PGHS-2 (r = 0.86) and we saw an increase in PGHS-2 mRNA in response to PGE2, the product of PGES-1. This may account for the strong relationship between PGHS-2 and PGES-1. Indeed, PGE2 has been reported to increase PGHS-2 mRNA stability in other tissues (Faour et al., 2001Go; Tamura et al., 2002Go) and the administration of nimesulide, a PGHS-2 inhibitor, to labouring sheep reduced myometrial PGHS-2 mRNA expression (Wu et al., 1998Go).

Sheep myometrial expression of PGES mRNA showed a tendency to reduce around the time of labour (Palliser et al., 2004Go). In humans, PGES expression was similar in preterm and term samples obtained from the lower uterine segment before and after the onset of labour studied by immunohistochemistry, western analysis and in situ hybridization (Giannoulias et al., 2002Go). Neither study differentiated between the types of PGES and therefore may not have identified more subtle changes in expression. In our study, we found that PGES-1 mRNA expression was greater in the lower than in the upper segment and that in the lower segment, PGES-1 mRNA expression was increased with the onset of labour. Further, we found that PGES-1 mRNA levels related closely to those of IL-1ß (r = 0.82) and that IL-1ß increased PGES-1 mRNA expression in primary cultures of human uterine smooth muscle cells. These data suggest that IL-1ß increases PGES mRNA expression, leading to an increase in PGE2 levels, which in turn increases PGHS-2 mRNA levels perhaps via an effect on PGHS-2 mRNA stability. What proportion of the IL-1ß-induced increase in PGHS-2 mRNA levels in uterine smooth muscle cells is mediated via its increase of PGE2 is uncertain, but in other tissues this has been given as a potential explanation for the relatively modest effects of IL-1ß on a PGHS-2 promoter construct (Tamura et al., 2002Go).

There was a relatively greater expression of the PGE2 synthetic enzyme mRNA in the lower segment. Given that the lower segment is under constant tension, stretch would seem to be the prime candidate for the co-ordinated increase in PGE2 synthetic enzyme mRNA expression in this site. However, we found that only PGHS-2 mRNA expression increased in response to stretch as we have previously reported (Sooranna et al., 2004Go). In contrast, cPLA2 mRNA expression was increased by stretch of the human amnion (Terakawa et al., 2002Go), but our data are consistent with those of Korita et al. (2002)Go who found that cyclical stretch of primary cultures of human uterine myocytes did not increase cPLA2. Perhaps the sequence of events is that stretch of the lower segment increases the expression of IL-8 (Loudon et al., 2004Go), resulting in the previously described inflammatory cell infiltrate (Osman et al., 2003Go). The activated neutrophils release inflammatory cytokines, and these in turn promote the expression of the enzymes involved in PGE2 synthesis. This is consistent with the increases in uterine smooth muscle cell expression of cPLA2, PGHS-2 and PGES-1 mRNA in response to IL-1ß described in this study. However, while each of the key enzymes in the PGE2 synthetic pathway relate to each other, only PGHS-2 and PGES-1 are associated with IL-1ß, suggesting the effect of IL-1ß on cPLA2 mRNA expression may be indirect.

These data support the hypothesis that the PGE2 synthetic enzymes are regulated in a co-ordinated fashion with the onset of labour and suggest that IL-1ß is the key factor. Further, they have shown that the lower segment of the uterus is the main site of PGE2 synthetic enzyme mRNA expression.


   Acknowledgements
 
This work was supported by a grant from Wellbeing, the Barclay Foundation and a donation from Will Greenwood.


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 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on March 21, 2006; resubmitted on June 1, 2006; accepted on June 7, 2006.


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