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Department of Maternal Fetal Medicine (S.R.S., N.E., M.R.J.), Imperial College Parturition Research Group, Imperial College School of Medicine, Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom; and Institute of Reproductive and Developmental Biology (J.A.Z.L., V.T., P.R.B.), Hammersmith Hospital Campus, London W12 0NN, United Kingdom
Address all correspondence and requests for reprints to: Dr. M. R. Johnson, 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, United Kingdom. E-mail: mark.johnson{at}imperial.ac.uk.
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-1ß is held to play a pivotal role in the inflammatory process of labor. Its production is increased in myometrium, cervix, decidua, and fetal membranes with labor (4, 10), and its levels are increased in amniotic fluid in the presence of chorioamnionitis and with the duration of labor (11, 12). It acts synergistically with IL-8 to increase prostaglandin production and uterine contractions in the rabbit (7), and in vitro in human myometrial cells, it increases prostaglandin H synthase 2 (PGHS-2) expression via p38 MAPK activation and increased nuclear factor 
B (NFB) DNA binding in myometrium and amnion (13, 14, 15). IL-1ß also increases IL-8 expression in fetal membranes and lower segment fibroblasts (8) and reduces prostaglandin dehydrogenase activity in the intact fetal membrane disc model (16).
Uterine stretch is held to play a key role in the onset of preterm labor associated with multiple pregnancy. Premature delivery occurs in 54% of twin and 88% of triplet pregnancies (17). This is supported by the observations that preterm labor is also increased in polyhydramnios (18), early birth is associated with a relatively greater birth weight (19), and abortion during the second trimester of pregnancy and labor at term can be induced by uterine distension achieved by the insertion and inflation of a 150-ml balloon (20, 21). Furthermore, animal data show that uterine stretch is responsible for the increase in contraction-associated protein (CAP) oxytocin receptor (OTR), PGHS-2, and connexin-43 (22, 23, 24, 25). We have shown that stretch of human uterine myocytes in vitro enhances the expression of OTR, PGHS-2, and IL-8 mRNA (26, 27, 28). However, the mechanisms whereby uterine stretch enhances CAP expression are unknown. In other cell types, stretch-associated changes in gene transcription have been related to activation of the MAPK pathway. Stretch of bronchial epithelial cells increased IL-8 release in an p38-dependent mechanism (29), vascular smooth muscle cells increased endothelin receptor type B in an ERK 1/2-dependent mechanism (30), and mesangial cells increased monocyte chemoattractant protein type 1 in an ERK 1/2-dependent mechanism (31).
In this study we investigated the effects of IL-1ß and stretch on MAPK activation to test the hypotheses that both IL-1ß and mechanical stretch increase the myometrial expression of the CAP PGHS-2 and IL-8 mRNA via MAPK activation and that their effects are synergistic.
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Materials and Methods |
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Biopsies (0.5 x 0.5 cm3) of term human myometrium were collected at the time of cesarean section from women not in labor [mean maternal age 31 yr (range 26–37)] in DMEM medium containing 100 mU/ml penicillin and 100 µg/ml streptomycin. Samples were stored at 4 C for no more than 3 h before cell preparation for culture. Tissue from cesarean section was removed from the upper margin of the incision made in the lower segment of the uterus. All specimens were obtained after patient consent, and the Riverside Research Ethics Committee approved the study.
Cell culture
Primary human uterine myocytes were isolated using a mixture of collagenases and cultured in DMEM, 7.5% fetal calf serum, 100 mU/ml penicillin, and 100 g/ml streptomycin in T75 in an atmosphere of 5% CO2-95% air at 37 C (32). Cells from passage 1–4 were trypsinized in 0.25% trypsin containing 0.02% EDTA in PBS and cultured in 6-well flexible-bottom culture plates precoated with collagen type I in 3 ml of DMEM. When cells were 85–95% confluent (d 3–4), old medium was removed and replaced with 3 ml of fresh medium supplemented with 7.5 mM HEPES with 1% fetal calf serum overnight. After 16–18 h these were subjected to a static stretch of 11% for 5, 10, 30, or 60 min using a strain unit (Flexcell International Corp., McKeesport, PA). Unstretched cells grown and treated similarly were aliquoted and used as controls. In some cases cells were preincubated with 10 µM U0126 [New England Biolabs (UK) Ltd., Hitchin, Hertfordshire, UK] for 2 h, 20 µM SP 600125 (Tocris Cookson Ltd., Bristol, UK) for 1 h, or 10 µM SB 203580 (Tocris Cookson) for 30 min before stretch. Some cells were also exposed to UV B irradiation using an F20T12/UV B source (wavelength 356 nm; Philips, Surrey, UK) for 30 min as a means of maximal stimulation of MAPKs (33, 34). At the end of the specified time, medium was removed and cells were either frozen in liquid nitrogen for extraction of RNA or lysed with protein extraction buffer for cytosolic or fixed for immunocytochemistry. More than 99% of cells remained attached to the 6-well culture plates after stretch protocols.
IL-1ß
The cells were plated and allowed to reach confluence. IL-1ß at the concentration of 1 ng/ml was added to the cells for 5, 10, 30, 60, and 360 min and the cells treated as above. For the combination of stretch and IL-1ß, the cells were incubated with IL-1ß for 360 min and were stretched for the last 60 min of incubation.
Quantitative RT-PCR
Total RNA was extracted and purified from myometrial cells grown in six-well flexible-bottom culture plates using RNAeasy minikit from QIAGEN Ltd. (Crawley, UK). After quantification, 1.0 µg was reverse transcribed with oligo dT random primers using Moloney leukemia virus reverse transcriptase (Applied Biosystems Ltd., Warrington, UK). Primer sets for PGHS-2, OTR, and glyceraldehyde-3-phosphate dehydrogenase were designed and obtained from Amersham Pharmacia Biotech (Little Chalfont, UK).
The primer sets produced amplicons of the expected size and flanked intron/exon junctions (Table 1
). 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., Lewes, West Sussex, 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 sec, 56–60 C for 10 sec, and 72 C for 10 sec 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 at which 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 glyceraldehyde-3-phosphate dehydrogenase. Conventional PCR was performed using Ampli-Taq Gold DNA polymerase (Applied Biosystems). 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.
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After stretch protocols, media were removed and the cells washed once with ice-cold PBS. Cells from each well (1 x 106) were lysed in 0.2 ml of a buffer containing 20 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1% Triton X-100, 1 mM EDTA, 1 mM EGTA, 2.5 mM Na pyrophosphate, 1 mM ß-glycerophosphate, 2 mM dithiothreitol, 1 mM Na3VO4, 1 mM phenylmethylsulfonyl fluoride, and 1 µg/ml leupeptin. After a further 5-min incubation on ice, the cells were scraped off the plate, transferred to microcentrifuge tubes, aliquoted, and frozen at –80 C. Protein concentrations were determined by protein assay (Bio-Rad Laboratories, Hercules, CA) and BSA reference standards. Electrophoresis was carried out on 15-µg aliquots of protein samples, in 2x loading buffer [4% sodium dodecyl sulfate, 20% glycerol, 10% 2-mercaptoethanol, 0.004% bromophenol blue, and 0.125 M/liter Tris-HCl (pH 6.8)]. Samples were boiled for 5 min, quenched on ice, and subsequently run on a 10% sodium dodecyl sulfate-polyacrylamide gel (Bio-Rad Laboratories).
Western blotting was carried out after electrophoretic transfer in 25 mM/liter Tris, 192 mM/liter glycine, and 20% (vol/vol) methanol (pH 8.3) onto Hybond enhanced chemiluminescence nitrocellulose membrane (Amersham Life Science, Little Chalfont, UK). Membranes were blocked in 5% milk protein in 0.1% Tween 20-PBS for 1 h at room temperature. Specific rabbit polyclonal antibodies, directed against the phospho- or total immunogen, were used for MAPKs [New England Biolabs (UK)] at a dilution of 1:1000, and incubated overnight at 4 C. Membranes were washed in 0.1% Tween 20-PBS and then incubated with antigoat IgG-horseradish peroxidase secondary antibody at a dilution of 1:2000 for 1 h at room temperature. Enhanced chemiluminescence Western blotting detection was carried out using standard chemiluminescence protocols (Perbio Science UK Ltd., Tatenhall, Cheshire, UK). Protein band size was determined using a biotinylated protein ladder followed by horseradish peroxidase-linked antibiotin antibody [New England Biolabs (UK)] Rainbow-colored protein molecular-weight markers (Amersham Life Science). Antibody specificity was confirmed using positive controls. Exposure of cells to UV B irradiation (wavelength 356 nm) for 15 min was used as positive controls. Western autoradiographs were quantified by digital densitometry using the Image Master VDS gel documentation system and Image Master VDS software (Pharmacia Biotech, Uppsala, Sweden). Protein bands were digitized, ensuring that the range of pixel densities did not extend to either the minimum or maximum values. Mean pixel density for each band was assessed using a sample gate of the same size. To allow comparisons between blots prepared on different occasions, a single control sample was included on each blot. The final pixel density was adjusted to ensure that this control sample carried the same value for each blot. Loading was controlled with ß-actin throughout.
Statistical analysis
The data were analyzed by t tests and ANOVA using SPSS (version 10.0; SPSS Inc., Chicago, IL). Differences were considered statistically significant at P < 0.05.
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Results |
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). The peak phosphorylation differed among MAPK types. ERK1/2 phosphorylation increased progressively, peaked at 30 min, and remaining elevated at 60 min (P < 0.05 vs. baseline at t = 10, 30, and 60 min); JNK-1 phosphorylation peaked at 5 min (P < 0.05 vs. baseline at t = 5 and 10 min); JNK-2/3 phosphorylation peaked at 5 min (P < 0.05 vs. baseline at t = 5 only); and p38 phosphorylation increased progressively with time (P < 0.05 vs. baseline at t = 30 and 60 min (Fig. 1).
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). ERK1/2 phosphorylation increased significantly at 30 min and had returned to baseline by 360 min (P < 0.05 vs. baseline at t = 30 min; Fig. 2A). Phosphorylation of JNK-2/3 was increased at 30 min only (P < 0.05 vs. baseline at t = 30 min; Fig. 2B). Phosphorylation of p38 was increased at 5 and 30 min (P < 0.05 vs. baseline at t = 5 and 30 min; Fig. 2C).
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) and reduced the stretch-induced increase in PGHS-2 and IL-8 mRNA (Fig. 4, for all P < 0.05 vs. stretched cells). Inhibition of JNK with SP 600125 blocked the stretch-induced phosphorylation of JNK-1 (Fig. 3B) but had no effect on the stretch-induced increase in PGHS-2 and IL-8 mRNA (Fig. 4). Inhibition of p38 using SB 203580 reduced p38 phosphorylation (Fig. 3C) and lessened the stretch-induced increase in PGHS-2 and IL-8 mRNA (P < 0.05 for both; Fig. 4).
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) and reduced the IL-1ß-induced increase in PGHS-2 and IL-8 mRNA (for all P < 0.05 vs. unstimulated cells; Fig. 6). Inhibition of JNK with SP 600125 blocked the IL-1ß-induced phosphorylation of JNK-2/3 (Fig. 5B) but had no effect on the IL-1ß-induced increase in PGHS-2 and IL-8 mRNA (Fig. 6). Inhibition of p38 using SB 203580 reduced p38 phosphorylation (Fig. 5C) and lessened the IL-1ß-induced increase in PGHS-2 but not IL-8 mRNA (P < 0.05 for PGHS-2; Fig. 6).
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). In the case of both JNK and p38, prior exposure to IL-1ß appeared to reduce their stretch-induced phosphorylation (Fig. 7, B and C). There was no additive effect of the combination of IL-1ß and stretch on PGHS-2 and IL-8 mRNA expression (Fig. 8).
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Discussion |
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Several studies have investigated MAPK in the rat myometrium. The first study suggested that ERK activity increased with advancing gestation and then declined immediately before the onset of parturition (35). Two subsequent papers showed that although ERK expression remained constant throughout rat pregnancy, its activity increased toward the end of pregnancy and rose again with the onset of labor (36, 37). In the first study, pregnancy was allowed to occur in one but not the other uterine horn and the increase in ERK activity was confined to the gravid horn. This suggests that ERK activation was a function of mechanical stretch. In the second study, the authors confirmed the increase in ERK activity with advancing pregnancy and a further increase with the onset of labor by studying the phosphorylation of an ERK-specific site on caldesmon (37). There are relatively few studies of MAPK in human myometrium and none relating MAPK activity to gestational age or the onset of labor. IL-1ß-induced PGHS-2 expression in human myometrial cells is inhibited by a p38 antagonist (13) and has been associated with ERK2 and JNK activation (38). In nonpregnant human myometrial cells, urocortin has been shown to activate ERK1/2 via Gq (39), and treatment with combination of estrogen and progesterone reduces ERK1/2 phosphorylation (40). Our data and those of Bartlett et al. (13) have demonstrated an effect of MAPK inhibition and suggest that MAPK may play an important role in myometrial PGHS-2 expression.
Stretch of primary cultures of rat myometrial cells in vitro resulted in activation of all three types of MAPK and the expression of c-Fos (36). The activation of all three MAPKs was found to be necessary for the optimal expression of c-Fos (36). In vivo, in the unilaterally pregnant rat model, MAPK activation and c-Fos expression is confined to the gravid horn (36, 41), further supporting the role of stretch in MAPK activation. Our data confirm that in the human myometrial cells also, stretch is associated with MAPK activation. ERK activation is sustained by stretch, whereas that of p38 is acute. The difference may reflect different physiological actions/roles. Although we have not studied c-Fos or other activator protein-1 (AP-1) protein expression in this study, we previously found AP-1 activation in association with stretch of human myometrial cells (27), and in the present study, we found that activation of both ERK1/2 and p38 were important in the stretch-induced increase in both PGHS-2 and IL-8 mRNA expression. Given that both PGHS-2 and IL-8 have AP-1 sites in their promoter regions, it is possible that in human myometrial cells, optimal stretch-induced activation of AP-1 requires only ERK1/2 and p38.
As described above, IL-1ß has been reported to stimulate PGHS-2 mRNA expression in myometrial cells in a p38-dependent mechanism (13), and that IL-1ß treatment of myometrial cells is associated with ERK and JNK activation (39). In other tissues, such as a gastric cancer cell line and bronchial epithelial cells, IL-1ß-induced increase in PGHS-2 is dependent on both ERK and p38 activation (42, 43). Similarly, other ligands increasing PGHS-2 expression in other tissues, such as endothelin in vascular smooth muscle cells and epithelial growth factor in chondrocytes, act via both ERK and p38 (44, 45). We examined the effects of specific inhibitors of ERK1/2, p38, and JNK. We found that for both stretch and IL-1ß, increased PGHS-2 expression was dependent on both ERK1/2 and p38 activation but independent of JNK activation. These data are consistent with mechanisms of action of IL-1ß on PGHS-2 expression described above.
The pattern of JNK activation was distinct, depending on mode of stimulation. Stretch activated JNK-1, whereas IL-1ß activated JNK-2/3. However, the JNK inhibitor had no effect on cyclooxygenase-2 or IL-8 mRNA expression in response to either stimulus. We investigated one level of stretch and one concentration of IL-1ß; therefore, it is possible that JNK activation is important at higher or lower levels of either stimulus. Indeed, in primary cultures of rat myometrial cells, stretch-induced (25% stretch) activation of c-Fos was dependent on activation of all three types of MAPK (36).
IL-8 release in different tissues and in response to various agents has been related to MAPK activation. Infection of pulmonary epithelial cells with adenovirus increases IL-8 release, and this is blocked by both MEK 1/2 inhibitors and the expression of a mutated form of Raf. These data identify Raf, MEK, and ERK as key steps in the expression of IL-8 by pulmonary epithelial cells in response to adenoviral infection (46). In both intestinal and bronchial epithelial cells, TNF
increased IL-8 mRNA expression and synthesis in an ERK- and p38-dependent mechanism (47, 48). In the study of Li et al. (48), NFB was also found to be activated and to play a role in the increased IL-8 synthesis; however, we found no evidence of NFB activation by stretch in human myometrial cells (27). In contrast to our data, stretch of alveolar epithelial cells increased IL-8 mRNA expression and protein synthesis via JNK and NFB (49). In the last study, stretch did induce a transient activation of ERK and p38, but blocking their activation had no effect of the stretch-induced increase in IL-8 mRNA and protein, whereas the expression of a dominant negative form of stress-activated protein kinase, the immediate up-stream activator of JNK, blocked the stretch-induced increase in IL-8 expression. The differences between the results of this study and our own may relate to tissue type, i.e. epithelial cells and smooth muscle cells, because stretch of human airway smooth muscle cells results in increase IL-8 mRNA expression and protein synthesis through activation of ERK1/2 and p38 (50). Our inhibitor data confirmed that stretch-induced increases in IL-8 expression were dependent on ERK1/2 and p38 activation but independent of JNK activation, consistent with the concept that the mechanisms responsible for stretch-induced changes in gene transcription vary in different tissue types.
The increase in IL-8 mRNA expression in response to IL-1ß is dependent on ERK1/2 and independent of either p38 or JNK activation. This contrasts with the effect of IL-1ß on PGHS-2 mRNA expression, which is ERK1/2 and p38 dependent, and the effect of stretch, which is also dependent on activation of both ERK1/2 and p38. Previous studies investigating IL-1ß- and IL-8 release variously reported that it was JNK dependent in human airway smooth muscle cells, p38 dependent in vascular smooth muscle cells, and both ERK1/2 and p38 dependent in retinal epithelial cells (51, 52, 53). However, in the studies of human airway and vascular smooth muscle cells, only a JNK and a p38 inhibitor, respectively, were used, meaning that the potential roles of the other MAPK types were not investigated.
The lack of a synergistic effect and stretch on either PGHS-2 or IL-8 mRNA expression contrasts to the data obtained from rabbit tendon cells in which stretch and IL-1ß acted synergistically to increase stromelysin release (54). The conditions were dissimilar in these rabbit studies in that 5% stretch was applied at a frequency of 0.33 Hz as opposed to being the static stretch used in our studies. It is possible that the concentration of IL-1ß used in our study resulted in maximal stimulation of PGHS-2 and IL-8 mRNA expression and that synergy may be seen with lower concentrations of IL1ß. Alternatively, the IL-1ß stimulation of MAPK may have triggered mechanisms designed to limit the duration or effect of MAPK activation; these may include the expression of MAPK phosphatase, which dephosphorylate MAPK, or the expression of phosphoprotein enriched in astrocytes, 15 kDa, which prevents the nuclear translocation of MAPK. These possibilities await further study.
These data demonstrate that both stretch and IL-1ß act through MAPK to increase PGHS-2 and IL-8 expression but do not act synergistically. The observation that amniotic IL-1ß levels are increased by uterine distension used to induce cervical ripening (55) raises the possibility that some of the effects of longer-term stretch may be mediated through increased IL-1ß levels.
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Footnotes |
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First Published Online March 22, 2005
Abbreviations: CAP, Contraction-associated protein; JNK, c-Jun N-terminal kinase; MEK, MAPK kinase; NFB, nuclear factor B; OTR, oxytocin receptor; PGHS-2, prostaglandin H synthase 2.
Received July 15, 2004.
Accepted March 14, 2005.
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References |
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and interleukin-1ß in preterm and term human parturition. Am J Reprod Immunol 27:17–23
B and AP-1 are required for cyclo-oxygenase 2 gene expression in amnion epithelial cell line (WISH). Mol Hum Reprod 6:561–565 in intact term fetal membranes. Placenta 19:625–630[CrossRef][Medline]
and R2ß CRH receptor subtypes and stimulation of Gq-proteins. Mol Endocrinol 14:2076–2091B-inducing kinases. Am J Physiol Lung Cell Mol Physiol 285:L464–L475
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