Molecular Human Reproduction, Vol. 7, No. 5, 475-481,
May 2001
© 2001 European Society of Human Reproduction and Embryology
Implantation and pregnancy |
Effects of platelet-activating factor on cytokine production by human uterine cervical fibroblasts
Department of Obstetrics and Gynecology, Oita Medical University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan
Abstract
Platelet-activating factor (PAF), a lipid that acts as a potent proinflammatory mediator, is involved in several reproductive processes including parturition. To investigate the effects of PAF on expression of various cytokines by cultured human uterine cervical fibroblasts obtained at term prior to labour, Northern blot analyses and enzyme-linked immunosorbent assays were performed. C-PAF, a stable analogue of PAF, increased expression of interleukin-6 and -8 mRNA in a dose-dependent manner (10-10 to 10–8 mol/l of C-PAF), and the expression peaked within 4 h. The corresponding protein concentrations were increased in culture media. Monocyte chemoattractant protein-1 mRNA showed marked induction by 10–8 mol/l of C-PAF; this peaked by 4 h and was followed by an increase in the protein concentration. Another cytokine, RANTES (regulated upon activation, normal T cell expressed and secreted) showed marked mRNA induction by 10–8 mol/l of C-PAF, and continued to increase in a time-dependent manner until 24 h. The protein concentration was correspondingly increased in the medium. The PAF-induced cytokine production was abolished by co-incubation with WEB 2170, a specific PAF receptor antagonist. PAF may stimulate local production of cytokines which may induce migration of leukocytes and accelerate collagenolysis in the uterine cervix, thus contributing to cervical ripening during parturition.
cervix/cytokines/fibroblasts/platelet-activating factor/platelet-activating factor receptor
Introduction
Uterine cervical ripening is a dramatic change in cervical tissue resulting from an inflammatory reaction and collagenolysis that occurs within a short time during parturition (Junqueira et al., 1980
). Various cell types in the cervix, including leukocytes, fibroblasts, and endothelial cells, are able to produce a variety of bioactive molecules including inflammatory cytokines and matrix metalloproteinases (MMP). Cytokines, such as interleukin (IL)-1, IL-8, and tumour necrosis factor-
(TNF-), have been reported to induce cervical ripening in guinea pigs (Chwalisz et al., 1994), rabbits (Uchiyama et al., 1992; Maradny et al., 1996) and humans (Barclay et al., 1993; Osmers et al., 1995; Ogawa et al., 1998).
Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn- glycero-3-phosphocholine) is a potent proinflammatory lipid mediator that is produced by macrophages, polymorphonuclear leukocytes, basophils, platelets, endothelial cells, and other cell types (Chao and Olson, 1993; Narahara et al., 1996). PAF is known to promote neutrophil chemotaxis (O'Flaherty et al., 1981; Kuijpers et al., 1992), and has been implicated in various inflammatory diseases such as bronchial asthma, gastrointestinal ulceration, and necrotizing enterocolitis (Chao and Olson, 1993; Narahara et al., 1996). PAF has recently been suggested to be involved in human parturition (Narahara et al., 1996), and its concentrations have been found to be increased in amniotic fluid during labour (Billah and Johnston, 1983). PAF stimulates fetal membranes to produce prostaglandin E2 (PGE2) (Morris et al., 1992; Alvi et al., 1999), which causes myometrial contraction (Zhu et al., 1992). Although we have recently demonstrated the effect of PAF on MMP-1 production in human uterine cervical fibroblasts (Sugano et al., 2000), a role for PAF has not been established in cervical ripening.
PAF induces expression of IL-6 and IL-8 in human lung fibroblasts (Roth et al., 1996; Tamm et al., 1998). IL-6 and IL-8 are important participants in parturition as well as in the pathophysiology of chorioamnionitis (Romero et al., 1990; Mitchell et al., 1991). Mitchell et al. (1991) have demonstrated that IL-6 stimulates PGE2 production by cultured amnion cells and decidual cells. Romero et al. (1990) have detected elevated IL-6 concentrations in amniotic fluid obtained from patients with preterm labour caused by infection; in this circumstance IL-6 may induce uterine contractions via stimulation of prostaglandin production by fetal membranes. IL-8 has also been closely linked to cervical ripening (Uchiyama et al., 1992; Barclay et al., 1993; Chwalisz et al., 1994; Osmers et al., 1995; Maradny et al., 1996; Ogawa et al., 1998; Sennstrom et al., 2000; Winkler et al., 2000). We have also reported an increase in the concentration of IL-8 in cervicovaginal fluid during pregnancy (Tanaka et al., 1998).
Monocyte chemoattractant protein-1 (MCP-1) and RANTES (regulated upon activation, normal T cell expressed and secreted) are members of the CC subfamily of chemokines, and attract mainly monocytes and T cells respectively (Schall et al., 1990; Yoshimura and Leonard, 1990). Although MCP-1 and RANTES have been shown to be secreted by endometrium (Arici et al., 1995; Hornung et al., 1997; Nasu et al., 1999) and placenta (Kelly et al., 1997; Denison et al., 1998), the production of these chemokines in the cervix has not been studied.
Biological effects of PAF have been shown to be mediated through the PAF receptor, which has been identified in human leukocytes, lung, heart, brain, skin, intestine, spleen, kidney and placenta (Honda et al., 1991; Nakamura et al., 1991; Ye et al., 1991; Chao and Olson, 1993). The PAF receptor has also been reported to be present in human myometrium (Zhu et al., 1992) and endometrium (Ahmed et al., 1998). The human PAF receptor gene produces two different species of mRNA (Mutoh et al., 1993), a tissue-type transcript (Mutoh et al., 1994a) and a leukocyte-type transcript (Mutoh et al., 1994b). Although both transcripts contain the same coding region, indicating that both gene products are identical, their expression is controlled by different promoters. The promoter region of the tissue-type transcript has oestrogen-responsive elements (ERE), through which oestrogen up-regulates transcriptional activity (Mutoh et al., 1994a).
We previously demonstrated that PAF stimulates cytokine production by human endometrial stromal cells (Nasu et al., 1999). We have also shown PAF receptor mRNA expression in cultured human uterine cervical fibroblasts (Sugano et al., 2000). In the present study, we investigated the effects of PAF on synthesis of IL-6, IL-8, MCP-1 and RANTES in cultured cervical fibroblasts in order to understand the role of local cytokine induction by PAF in the process of cervical ripening.
Materials and methods
Reagents
In all the present studies, we used C-PAF, the non-metabolizable analogue of PAF (1-O-hexadecyl-2-N-methylcarbamyl-sn-glycero-3-phosphocholine), which was purchased from Biomol Research Laboratories (Plymouth Meeting, PA, USA). Since PAF is inactivated in a short time by PAF-acetylhydrolase (Narahara et al., 1996), the effect of PAF itself has not been accurately investigated especially in time course experiments. C-PAF has been used in some past studies that have investigated the effects of PAF (Bazan et al., 1993; Nasu et al., 1999; Sugano et al., 2000).
Recombinant human IL-1ß and TNF- were purchased from R&D Systems (Minneapolis, MN, USA). WEB 2170, a PAF receptor antagonist, was kindly provided by Boehringer Ingelheim (Biberach, Germany).
Tissue preparation
Human pregnant uterine cervical tissues were obtained from the uterine low segment wound by cutting into thin slices from seven patients (aged 25–36 years) at term, before the onset of labour, at the time of Caesarean section. Indications for Caesarean section included cephalopelvic disproportion, a history of prior Caesarean sections, or fetal distress. There was no significant difference in cervical score (Bishop score <4) among the patients. The study had the approval of our Ethics Committee. Informed consent was obtained from each patient, and procedures were performed at the Oita Medical University Hospital.
Cell culture
Tissue samples were immediately washed free of blood in sterile phosphate-buffered saline (PBS) supplemented with antibiotics. The samples were cut into small pieces and digested with 200 U/ml collagenase (Gibco BRL, Gaithersburg, MD, USA) in PBS with gentle stirring for 1 h at 37°C. The collagenase-dispersed cells were filtered through a sterile 80 µm wire sieve, collected by low-speed centrifugation and washed twice with Dulbecco's modified Eagle's medium (DMEM) (Nissui Pharmaceutical, Tokyo, Japan). Cells were then cultured with DMEM supplemented with 10% (vol/vol) heat-inactivated fetal bovine serum (FBS) (JRH Biosciences, Lenexa, KS, USA), 100 U/ml penicillin (Gibco BRL), and 100 µg/ml streptomycin (Gibco BRL) at 37°C in a humidified atmosphere of 5% CO2. The culture medium was replaced every 4 days. Cells were passed by standard methods of trypsinization and used for experiments at the 4th to the 6th passages.
To determine that the cells were fibroblasts, immunocytochemistry was carried out by indirect immunofluorescence staining. The cells were cultured in a Chamber Slide System (Nalge Nunc International, Naperville, IL, USA), and then fixed with ice-cold methanol. The slides were incubated for 1 h with mouse monoclonal first antibodies (described below) after blocking with 1% bovine serum albumin (BSA) (Sigma, St Louis, MO, USA) to exclude non-specific staining, followed by rinsing three times in PBS for 5 min each. Slides were then incubated with a fluorescein-conjugated donkey anti-mouse IgG antibody (Jackson Immunoresearch, West Grove, PA, USA) at a dilution of 1:100, washed three times in PBS for 5 min each, and mounted with Vectashield (Vector Laboratories, Burlingame, CA, USA). All incubations and washes were performed at room temperature. Samples were viewed with a Zeiss Axiophot epifluorescence microscope (Carl Zeiss, Tokyo, Japan) equipped with filters to selectively display fluorescein fluorescence. These cells were stained with a monoclonal antibody against human beta-subunit of prolyl 4-hydroxylase (Biomeda, Foster City, CA) which is specific for human fibroblasts, and with a monoclonal antibody against human vimentin (Dako, Glostrup, Denmark) by the method as described above (data not shown). The cells were not stained by monoclonal antibodies against human cytokeratin (Dako), CD68 (Dako), smooth muscle cell actin (Dako), factor VIII (Dako), and leukocyte common antigen (Dako) (data not shown). No contamination by epithelial cells, macrophages, smooth muscle cells, and endothelial cells was present in our cell cultures.
The fibroblasts underwent repeated passage in culture and trypsinization before they were plated in culture dishes of 92 mm in diameter (Nalge Nunc International) for isolation of RNA, or were plated in 6-well culture plates (Nalge Nunc International) for measurement of cytokine proteins in the medium. Each cell preparation from different patients was cultured separately, and each experiment was repeated with a minimum of three preparations. There was no heterogeneity among different culture cells. There was no significant difference in the cell growth, expression of PAF receptor, and the response to PAF between the different cell preparations.
RNA isolation
Total RNA was isolated from confluent cultures of cervical fibroblasts with Trizol Reagent (Gibco BRL) using a guanidinium thiocyanate phenol-chloroform method according to the manufacturer's instructions. Total RNA was quantified by measuring absorbance at a wavelength of 260 nm.
Preparation of probes and Northern blot analyses
Total RNA (3 µg) from IL-1ß-stimulated cervical fibroblasts was reverse transcribed using a cDNA synthesis kit (Takara, Tokyo, Japan). In brief, a reaction volume of 20 µl was prepared containing 50 U of Rous-associated virus-2 reverse transcriptase, 2 µg of oligo (dT)18 primer, 1 mmol/l each of dATP, dCTP, dGTP, and dTTP, and 20 U of RNase inhibitor in a reverse transcription (RT) buffer (50 mmol/l Tris–HCl pH 8.3, 75 mmol/l KCl, 3 mmol/l MgCl2, and 10 mmol/l dithiothreitol). The mixture was incubated at 42°C for 60 min.
Polymerase chain reaction (PCR) amplification was then carried out in a 50 µl reaction volume containing 2 µl from each reverse transcription reaction, 5 U of Taq DNA polymerase (Takara), 0.5 µmol/l each of the sense and antisense primers, 0.2 mmol/l each of dATP, dCTP, dGTP, and dTTP (Takara), and a Taq buffer (10 mmol/l Tris–HCl pH8.0, 50 mmol/l KCl, 2 mmol/l MgCl2) (Takara). The reaction was amplified for 30 cycles as follows: 94°C for 1 min, 59°C for 1 min, and 72°C for 1 min. Primer sets were chosen to amplify a 491 bp fragment of the human MCP-1 cDNA, a 276 bp fragment of the human RANTES cDNA, and a 983 bp fragment of the human glyceraldehyde 3-phosphate dehydrogenase (GAPDH) cDNA. The MCP-1 primer sequences were: 5'-CCC TTC TGT GCC TGC TGC TCA T-3' (sense primer) and 5'-TTT CCC CAA GTC TCT GTA TCT-3' (antisense primer). The RANTES primer sequences were: 5'-ATG AAG GTC TCC GCG GCA CGC CT-3' (sense primer) and 5'-CTA GCT CAT CTC CAA AGA GTT G-3' (antisense primer) (Matsukura et al., 1996). The GAPDH primer sequences were: 5'-TGA AGG TCG GAG TCA ACG GAT TTG GT-3' (sense primer) and 5'-CAT GTG GGC CAT GAG GTC CAC CAC-3' (antisense primer). To validate that the amplified cDNA was coding for MCP-1, RANTES, and GAPDH, these PCR products were cloned with a TA cloning kit (Invitrogen, Leek, The Netherlands), and direct sequence analysis was performed. These fragments were then used as probes for Northern analyses. Human IL-6 and IL-8 cDNA fragments used in Northern hybridization were as previously described (Nasu et al., 1999). The probes were labelled and purified with 32P using a Rediprime II random prime labelling system (Amersham Pharmacia Biotech) and a Sepharose-G50 column (Amersham Pharmacia Biotech).
Confluent cultures of cervical fibroblasts were placed in DMEM supplemented with 0.1% (wt/vol) BSA (Sigma) and treated with suboptimal concentrations (<10–7 mol/l) of C-PAF (Bazan et al., 1993; Alvi et al., 1999; Sugano et al., 2000) or such cytokines as IL-1ß and TNF- to examine the expression of IL-6, IL-8, MCP-1, and RANTES. Cultures were washed with PBS, and total RNA was isolated with Trizol Reagent (Gibco BRL) as described above. Denatured total RNA (10 µg in each well) was electrophoretically separated by size on a formaldehyde agarose-denaturing gel, transferred to a Hybond-N membrane (Amersham Pharmacia Biotech) by capillary action using 10xSSC solution (166.5 mmol/l NaCl and 166.5 mmol/l sodium citrate pH 7.0), and cross-linked to the membrane by ultraviolet light exposure. The membrane was prehybridized with Hybrisol I [50% formamide, 100 mmol/l NaCl, 100 mmol/l sodium citrate, 10% dextran sulphate, 1% sodium dodecyl sulphate (SDS), sheared DNA, and modified Denhardt's solution; Oncor, Gaithersburg, MD, USA] for 2 h at 42°C. Hybridizations were conducted for 16 h at 42°C in the same buffer with the various 32P-labelled random-primed cDNA probes (see probes). After hybridization, the membranes were washed twice in 2xSSC (33.3 mmol/l NaCl, 33.3 mmol/l sodium citrate pH 7.0)/0.1% (wt/vol) SDS for 20 min at room temperature and twice in 0.2xSSC (3.33 mmol/l NaCl, 3.33 mmol/l sodium citrate pH7.0)/0.1% (wt/vol) SDS for 30 min at 65°C. Autoradiography was performed at –80°C using Hyperfilm-MP (Amersham Pharmacia Biotech). Autoradiographic bands were quantified by densitometric scanning using a public domain program, NIH Image 1.61, developed at the US National Institutes of Health, Bethesda, MD, USA. Expression of mRNA for GAPDH was also quantified as an internal control.
Enzyme-linked immunosorbent assay (ELISA) for IL-6, IL-8, MCP-1, and RANTES
Approximately 1x106 cells/well were seeded on 6-well culture plates (Nalge Nunc International) in 2 ml of DMEM with 10% (vol/vol) FBS and cultured until fully confluent. After overnight serum starvation, the supernatants were replaced with 1 ml of DMEM supplemented with 0.1% (wt/vol) BSA, either alone or containing C-PAF (10–8 mol/l), and cultured for 24 h. Immunoreactive IL-6, IL-8, MCP-1, and RANTES in the culture media of cervical fibroblasts was quantified with an ELISA kit (R&D Systems) according to the manufacturer's instructions. Samples were diluted as necessary. In addition, to determine whether PAF increased the production of each cytokine by uterine cervical fibroblasts by interacting with the PAF receptor, cells were preincubated for 1 h with a suboptimal concentration (10–5 mol/l) of the specific antagonist WEB 2170 (Sugano et al., 2000) before C-PAF was added. The assay was performed in triplicate.
Statistical analysis
ELISA data are presented as mean ± SD of triplicate samples, and were evaluated by Student's t-test and the Bonferroni/Dunn test with the StatView 4.5 program (Abacus Concepts, Berkeley, CA, USA). Differences were considered statistically significant at a level of P < 0.05.
Results
Effects of PAF on expression of cytokine mRNA in human uterine cervical fibroblasts
Total RNA was isolated from cervical fibroblasts after incubation for 12 h with IL-1ß (1 ng/ml), TNF- (10 ng/ml), or C-PAF (10–8 mol/l). As shown in Figure 1, expression of IL-6, IL-8, MCP-1, and RANTES mRNA was increased by treatment with C-PAF to an extent in the range of that resulting from treatment with IL-1ß or TNF-. Treatment with higher concentrations such as 10–7 and 10–6 mol/l of C-PAF caused cultured cervical fibroblasts to die, and we were not able to isolate their RNA (data not shown).
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Expression of IL-6 and IL-8 mRNA was increased in the presence of increasing concentrations of C-PAF (10–10 to 10–8 mol/l, Figure 2
). C-PAF showed the strongest stimulatory effects at the concentration of 10–8 mol/l. MCP-1 and RANTES mRNA levels were only slightly increased above those in vehicle controls with 
10–9 mol/l C-PAF, but at 10–8 mol/l C-PAF, there was a marked increased expression of both cytokines.
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Figure 3
shows the kinetics of the cytokine mRNA expression. Expression of IL-6, IL-8, and MCP-1 mRNA was markedly induced within a short time (4 h), and remained high for up to 24 h with C-PAF treatment. After incubation with 10–8 mol/l of C-PAF for 4 h, the amounts of mRNA for IL-6, IL-8, and MCP-1 (expressed relative to GAPDH mRNA) increased 5.6-fold, 14-fold and 12-fold respectively beyond amounts in the time zero control. The level of RANTES mRNA was minimal at time zero, but induced at 4 h, with a time-dependent increase continuing up to 24 h.
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Effect of PAF on cytokine production by human uterine cervical fibroblasts
Cultured fibroblasts were incubated with C-PAF (10–8 mol/l) and/or WEB 2170 (10–5 mol/l). While IL-6, IL-8, and MCP-1 production was detected even in supernatants from control cultures, RANTES were below detectable levels (<5 pg/ml) in supernatants from controls and from cultures incubated with WEB 2170 for 24 h. C-PAF significantly induced production of IL-6, IL-8, and MCP-1 beyond that in vehicle controls (IL-6, 3967 ± 108 versus 856 ± 72 pg/ml, P < 0.0001; IL-8, 46 990 ± 9095 versus 2527 ± 346 pg/ml, P < 0.0001; and MCP-1, 80 510 ± 3239 versus 9472 ± 289 pg/ml, P < 0.0001; Figure 4A-C
). RANTES secretion also showed marked induction by treatment with C-PAF (4597 ± 1345 pg/ml, Figure 4D). Preincubation with WEB 2170, a specific PAF receptor antagonist, abolished all C-PAF-induced increases in cytokine production (P < 0.0001, Figure 4). WEB 2170 alone had no significant effect on cytokine production by cervical fibroblasts (Figure 4).
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Discussion
PAF has been suggested to be involved in parturition (Narahara et al., 1996). The concentration of PAF in amniotic fluid is limited to trace amounts before labour, but during parturition it increases markedly (Billah and Johnston, 1983). PAF is inactivated mainly by PAF-acetylhydrolase, which converts PAF into biologically inactive lyso-PAF and regulates PAF levels in both the de-novo and the remodelling pathways of PAF formation (Chao and Olson, 1993; Narahara et al., 1996). We previously suggested an autocrine or paracrine regulation of PAF concentrations in decidua (Narahara et al., 1993), as amnion cells and decidual macrophages synthesize PAF, while decidual macrophages, located at the maternal-fetal interface, secrete PAF-acetylhydrolase (Narahara et al., 1993, 1996). PAF may play an important role in uterine contraction via both the PAF-induced stimulation of PGE2 production by the chorion-decidua (Morris et al., 1992; Alvi et al., 1999) and induction of myosin light chain phosphorylation following an increase in intracellular Ca2+ concentration in myometrial smooth muscle cells (Zhu et al., 1992).
In the present study, we demonstrated that C-PAF induces mRNA and protein expression for IL-6, IL-8, MCP-1, and RANTES in cultured human uterine cervical fibroblasts. These observations suggest that PAF may be involved in the regulation of the cytokine network between cervical fibroblasts and other cell types in the uterine cervix. We previously reported that C-PAF stimulates production of cytokines such as IL-6, IL-8, macrophage colony-stimulating factor, macrophage inflammatory protein-1, and TNF- by human endometrial stromal cells (Nasu et al., 1999). Polymorphonuclear leukocytes, which infiltrate into the stroma of the cervix at the time of parturition (Junqueira et al., 1980; Osmers et al., 1992; Bokstrom et al., 1997; Knudsen et al., 1997), can produce PAF as well as various inflammatory cytokines. PAF also induces migration of leukocytes into the cervix as do cytokines produced by inflammatory cells. The inflammatory cells, and possibly also cervical stromal cells, accelerate collagenolysis by producing MMP (Nagase et al., 1991). We have demonstrated that PAF induces MMP-1 expression in cultured human uterine cervical fibroblasts (Sugano et al., 2000). Consequently, paracrine and autocrine effects of various inflammatory mediators including PAF may enhance collagenolysis to induce cervical ripening.
We previously showed expression of PAF receptor mRNA and protein in cultured cervical fibroblasts (Sugano et al., 2000). Also in the present study, we demonstrated that WEB 2170, a specific PAF receptor antagonist, blocked the stimulatory effect of PAF on the production of IL-6, IL-8, MCP-1, and RANTES in vitro, further suggesting the specific PAF receptor-mediated effect. Considering that the uterus is exposed to large amounts of oestrogen, especially during parturition, and that oestrogen up-regulates PAF receptor expression (Mutoh et al., 1994a), PAF receptors might be increased in the cervix during pregnancy. This increased expression of the PAF receptor may lead to augmentation of PAF-induced cytokine production. We are now investigating the mechanisms regulating the PAF receptor expression during pregnancy.
In this study, C-PAF increased levels of mRNA for IL-6 and IL-8 in a dose-dependent manner from 10–10 to 10–8 mol/l, reaching a peak level by 4 h. It has been reported (Roth et al., 1996) that IL-6 and IL-8 mRNA levels peaked at 1-2 h and 4-6 h respectively in response to addition of 10–8 mol/l of C-PAF to human lung fibroblasts. In our study, expression of IL-6 and IL-8 mRNA remained high up to 24 h. Our study also demonstrated that MCP-1 and RANTES are expressed in cervical fibroblasts, suggesting that these chemokines, which are chemotactic for monocytes and T cells respectively, might also take part in cervical ripening by accelerating the inflammatory response during parturition. The kinetics of MCP-1 mRNA expression in response to C-PAF, with a peak at 4 h, was similar to those of IL-6 and IL-8 mRNA. Interestingly, RANTES mRNA expression increased more slowly, with a continuing time-dependent increase up to 24 h. We recently demonstrated the RANTES expression in human endometrial stromal cells, and showed that also in these cells RANTES was not detected in the control culture media (Arima et al., 2000). Slow induction of RANTES mRNA expression by IL-1ß in human bronchial epithelial cells has also been demonstrated (Manni et al., 1996). Their kinetic data showing the transcript to be detectable at 4 h and peaking at 24 h is consistent with our findings.
In summary, we demonstrated that PAF increases IL-6, IL-8, MCP-1, and RANTES expression in stromal cells of pregnant human uterine cervices. These findings suggest that PAF may accelerate collagenolysis by increasing local concentrations of cytokines that induce migration of leukocytes into the cervix, contributing to the promotion of cervical ripening during parturition.
Acknowledgements
We thank Ms Toshie Yoshida for assistance with cell culture. We also thank Ms Yuko Sato and Ms Chieko Kuga for their editorial assistance.
Notes
1 Current address: Department of Obstetrics and Gynecology, Oita National Hospital, 2-11-45 Yokota, Oita-city, Oita 870-0263, Japan 
2 To whom correspondence should be addressed. E-mail: sugano{at}oita-med.ac.jp
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Submitted on November 21, 2000; accepted on February 5, 2001.
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