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Original Studies |
Departments of Obstetrics and Gynecology (T.-L.E., K.S., K.N., J.J., O.Y., A.R.) and Bacteriology and Immunology, The Haartman Institute (A.R.), Helsinki University Central Hospital and University of Helsinki, FIN-00029 Helsinki, Finland
Address all correspondence and requests for reprints to: Dr. Ari Ristimäki, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, P.O. Box 140, FIN-00029 Helsinki, Finland. E-mail: Ari.Ristimaki{at}HUCH.fi
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF), induce the expression
of Cox-2 in amnion-derived WISH cells and in cells derived from chorion
and decidua (17, 18, 19, 20). In addition, IL-1ß and TNF stimulate the
synthesis of prostanoids in myometrial cells (21), which is at
least partially mediated by increased activity of phospholipase
A2 (22). However, in contrast to fetal membranes,
myometrial Cox-2 expression was not increased at the onset of labor
(23, 24, 25, 26).
Prostanoids transduce their signals via seven transmembrane receptors
that couple to different guanine nucleotide-binding (G) proteins and
downstream signal transduction systems (27). Knockout studies indicate
that the PGE2 receptor subtype
EP2 is involved with ovulation and/or
fertilization (28, 29), and the receptor for
PGF2 is important at the onset of labor by
inducing luteolysis in mice (30). In the uterus
PGF2 facilitates contractile signals via
PGF2 receptor (FP receptor), whereas
PGE2 can either contract via
EP1 and EP3 receptors or
relax via EP2 and EP4
receptors (31, 32). Interestingly, the expression pattern of prostanoid
receptors changes during pregnancy and at the onset of labor in human
myometrium (33, 34). However, very little is known about the factors
that regulate the expression of prostanoid receptors.
The purpose of this study was to investigate the expression of Cox-2 in human lower segment myometrium obtained from women in labor and those not in labor. We also examined the effect of proinflammatory cytokines on the expression of Cox-2 messenger ribonucleic acid (mRNA) and protein and on the expression of EP1–4, FP, and prostacyclin receptor (IP receptor) transcripts in cultured myometrial smooth muscle cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Myometrial tissues were collected from 25 healthy women at
gestation weeks 37–42. Ten women had been in labor for 6–22 h
(mean ± SEM, 14.3 ± 1.9 h), their cervix
had been opened (6.6 ± 0.9 cm, except patient 4 whose cervix was
closed), and 4–24 h (12.9 ± 2.1) had elapsed from the rupture of
fetal membranes. All women in labor had received oxytocin treatment.
Fifteen women underwent elective cesarean sections; they did not have
regular contractions, and their fetal membranes were intact. Myometrial
specimens (
1 cm3) were collected from the
upper edge of the uterine incision during lower segment cesarean
section with the approval of the local ethics committee. Informed
consent was obtained from all patients. Samples were first rinsed in
Dulbecco’s phosphate-buffered saline (PBS; HyClone Laboratories, Inc., Cramlington, UK), and then endometrial tissue was removed,
after which the myometrium was either processed for the tissue culture
(see below) or snap-frozen in liquid nitrogen and stored at -70°C
until analyzed. In addition, specimens of lower segment myometrium were
collected from patients in labor for immunohistochemical analysis (see
below).
Myometrial cell cultures
Myometrial cells were isolated from tissues obtained from either
lower segment elective cesarean sections at term (three separate cell
lines) or from the fundal part of the uterus of a nonpregnant patient
(age, 40 yr) undergoing hysterectomy for myomatous uterus. The
specimens were first dissected into small pieces and then digested with
freshly prepared collagenase (0.2%; type IV; Sigma, St.
Louis, MO) and trypsin (0.05%, Life Technologies, Inc.,
Paisley, Scotland) in DMEM supplemented with 20 mmol/L HEPES
(Life Technologies, Inc.), 2 mmol/L
L-glutamine, and antibiotics for 2 h in 37°C at 5%
CO2 in air. Then the suspension was centrifuged,
washed once with culture medium, and resuspended in the culture medium,
which contained DMEM supplemented with L-glutamine,
antibiotics, and 10% FCS (HyClone Laboratories, Inc.).
Primary cultures were grown in 75-cm2 tissue
culture flasks (Nunc, Roskilde, Denmark). The cells were used at
passages 2–7, and they exhibited positive staining for human smooth
muscle actin as detected by immunofluorescence (see below). Before each
experiment the confluent cultures were starved for 48 h in DMEM
supplemented with 0.5% FCS, and treated with or without IL-1ß
(0.01–10 ng/mL), TNF (100 ng/mL; R&D Systems, Minneapolis, MN),
phorbol 12myristate 13-acetate (PMA; 10 ng/mL;
Sigma), oxytocin (0.4 nmol/L; ICN Biomedicals, Inc., Aurora, OH), dexamethasone (1 µmol/L;
Sigma), NS-398 (15 µmol/L; Cayman Chemical Co., Ann
Arbor, MI), and/or indomethacin (10 µmol/L; Sigma) in
10-cm tissue culture dishes (Nunc) for 2–48 h.
RNA isolation and Northern blot analyses
Total RNA from tissue samples was extracted using the guanidine
isothiocyanate-cesium chloride method (35) and from cultured myometrial
cells with TRIzol reagent (Life Technologies, Inc.). For
Northern blot analysis, 20 µg RNA were denatured in 1 mol/L glyoxal,
50% dimethylsulfoxide, and 10 mmol/L phosphate buffer at 50°C for 60
min, and then electrophoresed through 1.2% agarose gel. The RNA was
transferred to nylon membranes (Micron Separation, Inc., Westborough,
MA). Blots were baked for 1 h at 80°C and cross-linked under UV
light for 6 min (Reprostar II UV, Camag, Muttenz, Switzerland).
Complementary DNAs (cDNAs) from human open reading frame of
EP1, EP3,
EP4, FP, and IP receptors were gifts from Merck
Frosst Canada, Inc. (Québec, Canada), and the cDNA for human
EP2 receptor open reading frame was a gift from
Dr. John W. Regan, University of Arizona (Tucson, AZ).
Prostanoid receptor cDNAs, human Cox-2 cDNA, and
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cDNA (36) were labeled
using [-32P]deoxy-CTP (DuPont-NEN Life Science Products, Boston, MA) and Prime-a-Gene kit
(Promega Corp., Madison, WI). Probes were purified with
nick columns (Pharmacia, Uppsala, Sweden) and used at 1 x
106 cpm/mL. Hybridizations were performed at
42°C for 16 h in solution containing 50% formamide, 6 x
SSC (standard saline citrate), 0.1% Ficoll, 0.1%
polyvinylpyrrolidone, 0.1% BSA, 100 µg/mL herring sperm DNA, 100
µg/mL yeast RNA, and 0.5% SDS. Membranes were washed three times at
50°C for 15 min each time in 0.1 x SSC and 0.1% SDS. Northern
blots were visualized by autoradiography and were quantitated using NIH
Image 1.57 on a Macintosh personal computer.
Immunofluorescence
For immunofluorescence, myometrial cells were grown on chamber slides (Nunc) and then treated with or without IL-1ß (10 ng/mL) or PMA (10 ng/mL) for 6 h. The cells were fixed with ice-cold acetone for 5 min, and then the chambers were washed three times with PBS for 10 min each time at room temperature. Nonspecific binding of antibodies was blocked with 1% BSA in PBS for 15 min. The samples were then incubated with a 1:40 dilution of antihuman Cox-2 polyclonal antibodies (Cayman Chemical) at room temperature for 30 min and washed with 1% BSA in PBS three times for 10 min. The secondary antibody (1:50 dilution), fluorescein isothiocyanate-conjugated goat antirabbit IgG (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA), was added and incubated for 30 min, and the samples were then washed with 1% BSA in PBS three times for 10 min each time. Normal rabbit IgG (30 µg/mL; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) was used as a control. Monoclonal antihuman smooth muscle actin antibody (1:50; DAKO Corp., Klostrup, Denmark) and fluorescein isothiocyanateconjugated rabbit antimouse Ig (1:40, DAKO Corp.) were used to confirm the purity of the myometrial smooth muscle cell cultures.
Western blotting
Myometrial cells were treated with or without IL-1ß or PMA for 6 h, after which they were lysed in RIPA buffer (150 mmol/L NaCl, 1% Nonidet P-40, 1% sodium deoxycholate, 0.1% SDS, 50 mmol/L Tris, and 1 mmol/L ethylenediamine tetraacetate, pH 8.0), supplemented with protease inhibitors aprotinin (1 µg/mL) and phenylmethylsulfonylfluoride (100 µg/mL), and centrifuged at 15,000 x g for 20 min. Protein concentration was measured with a BSA protein assay (Pierce Chemical Co., Rockford, IL). Proteins (100 µg) were resuspended in sample loading buffer [110 mmol/L Tris-HCl (pH 6.8), 2% SDS, 9% glycerol, 5% ß-mercaptoethanol, and 0.005% bromophenol blue] and separated by SDS (12%)-PAGE. The proteins were transferred electrophoretically to Hybond-C extra nitrocellulose membranes (Amersham Pharmacia Biotech, Aylesbury, UK). Nonspecific binding was blocked by Tris-buffered saline/Nonidet P40 (TBS-NP40)/5% low fat dry milk solution overnight at 4°C. For immunodetection, membrane was incubated with antimouse Cox-2 polyclonal IgG (1:1,000 dilution; Cayman Chemical) for 1 h at room temperature. The membrane was washed three times in TBS-NP40, and incubated with goat antirabbit antibodies conjugated to horseradish peroxidase (1:2,000 dilution) for 1 h at room temperature. After four washes with TBS-NP40, Cox-2 proteins were visualized by enhanced chemiluminescence (Amersham Pharmacia Biotech).
Immunohistochemistry
Formalin-fixed and paraffin-embedded specimens were sectioned (4–5 µm), deparaffinized, and microwaved for 2.5 min at 800 watts and for 15 min at 440 watts in 0.01 mol/L sodium citrate buffer (pH 6.0). The slides were immersed in 0.6% hydrogen peroxide in methanol for 30 min and then in blocking solution (0.01 mol/L Tris, 0.1 mol/L MgCl2, 0.5% Tween-20, 1% BSA, and 5% normal goat serum) for 1 h to block endogenous peroxidase activity and unspecific binding sites, respectively. Immunostaining was performed with an affinity-purified antimouse Cox-2 polyclonal antibody (Cayman Chemical) in a dilution of 1:250 in the blocking solution at 4°C overnight. The sections were thereafter treated with biotinylated secondary antirabbit antibodies in a dilution of 1:200 (Vectastain ABC kit, Vector Laboratories, Inc., Burlingame, CA), and antibody-binding sites were finally visualized by avidin-biotin peroxidase complex solution (ABComplex, Vectastain, Vector Laboratories, Inc.) and 3-amino-9-ethylcarbazole (Lab Vision Co., Fremont, CA). The counterstaining was performed with Mayer’s hemalum (Merck & Co., Darmstadt, Germany). Specificity was determined by preadsorption of the anti-Cox-2 antibodies using a Cox-2 control peptide (20 µg/mL; Cayman Chemical). Monoclonal antihuman smooth muscle actin antibody (1:1000) and rabbit antimouse immunoglobulin (1:200; Vector Laboratories, Inc.) were used for identification of the smooth muscle cells.
Assays for measuring the release of prostanoids from cultured myometrial cells
Myometrial cells were first incubated with the test agents for
6 h, after which the cells were washed once with PBS and incubated
further with arachidonic acid (10 µmol/L; Sigma) for 10
min. PGE2 and PGF2 were
analyzed by enzyme immunoassay (Cayman Chemical). 6-Keto
PGF1, a stable hydrolysis product of
prostacyclin (PGI2), was analyzed with RIA
employing specific antibodies (37) and a tritiated
6-keto-PGF1 (Amersham Pharmacia Biotech). The intra- and interassay coefficients of variation
were 8% and 14% (n = 10), respectively. Recovery of
6-keto-PGF1 added to culture medium was
92 ± 12% (mean ± SD; n = 10). Parallelism
of two dilutions of the unknown and the standard curve was a
prerequisite for acceptance of the assay.
Statistical analysis
The statistical significance of cell culture experiments was calculated for a single comparison using Student’s t test. For multiple comparison, the t test was used only if one-way ANOVA indicated a significant difference. Mann-Whitney U test was used to test for significant differences between the not in labor group and the in labor group. The Spearman correlation was used for calculating the significance of the correlation. All results are shown as the mean ± SEM, and P < 0.05 was selected as the statistically significant value.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Expression of Cox-2 mRNA was not
associated with the time from the beginning of regular contractions or
the rupture of fetal membranes (not shown). Immunohistochemical
detection of Cox-2 protein showed cytoplasmic staining in the smooth
muscle cells of the myometrium (Fig. 2).
Interestingly, there was little Cox-2 staining in the smooth muscle
cells of the veins, as shown in Fig. 2.
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). The
peak induction was obtained after incubation with IL-1ß (10 ng/mL)
for 6 h (Fig. 3A), at which time Cox-2 mRNA expression was
stimulated by 17.1 ± 1.5-fold (P < 0.0001), as
detected in three different myometrial cell lines, each tested in four
separate experiments (n = 12). Expression of Cox-2 transcript was
also induced by TNF and PMA, but not by oxytocin (Fig. 4A). An identical pattern of induction of
Cox-2 mRNA was also found in myometrial cell cultures isolated from
fundal part of the uterus from a nonpregnant patient (Fig. 4A). The
effect of IL-1ß on Cox-2 mRNA expression was blocked by
dexamethasone, but not by a Cox-2-selective inhibitor NS-398 (Fig. 4B).
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). To investigate whether IL-1ß
induced expression of enzymatically active Cox-2 protein, the cells
were treated with IL-1ß for 6 h, after which they were further
incubated in the presence of arachidonic acid (10 µmol/L) for 10 min.
Cox-2 converted arachidonic acid mainly to
6-keto-PGF1 and also to
PGE2 and PGF2 (Fig. 6A), which is consistent with previously
published data (21, 38, 39). Preincubation with IL-1ß (10 ng/mL) for
6 h stimulated the release of 6-keto-PGF1
by 9.1 ± 1.3-fold (P < 0.0001), as detected in
four separate experiments (n = 16). Consistent with our mRNA data,
TNF-, but not oxytocin, also induced the conversion of arachidonic
acid to 6-keto-PGF1 (Fig. 6B). IL-1ß-induced
conversion of arachidonic acid to 6-keto-PGF1
was blocked by the Cox-2-selective inhibitor NS-398, whereas the
nonselective inhibitor indomethacin also suppressed the basal,
presumably Cox-1-dependent, release of
6-keto-PGF1 (Fig. 6C). In addition,
dexamethasone inhibited IL-1ß-induced conversion of arachidonic acid
to 6-keto-PGF1 (not shown).
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). Basal expression of transcripts for
EP1, EP3,
EP4, FP, and IP was low or below the detection
limit (not shown). However, IL-1ß stimulated expression of
EP4 receptor mRNA (Fig. 7). The size of the major
human EP2 receptor transcript is 3.1–3.5 kb (40, 41), which is consistent with our data. Additional
EP2 receptor messages (2.5 and 4.5 kb) have also
been described (41). Our EP2 probe recognized a
message that may correspond to the 4.5-kb mRNA species, but as total
RNA was used in the Northern blot assay, we cannot exclude the
possibility of cross-hybridization to ribosomal RNA. The size of the
EP4 transcript was approximately 3.8 kb, which is
consistent with previously published data (42, 43).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-1ß has been shown to stimulate the production of prostanoids
in human myometrial cells (21, 44) by activating phospholipase
A2 (22), and recently, IL-1ß was also shown to
induce Cox-2 expression in an immortalized human myometrial smooth
muscle cell line (45). In our experiments, cultured human myometrial
smooth muscle cells expressed low or undetectable levels of Cox-2 mRNA
and protein, which both were induced by IL-1ß. IL-1ß-induced steady
state levels of the Cox-2 mRNA were elevated by 17-fold during
incubation for 6 h, which is a relatively high induction compared
to that in fetal membranes or cells derived from them (17, 46, 47).
IL-1ß-induced Cox-2 mRNA expression was evident after incubation for
2 h, reached its maximum by 6 h, and was still present after
48 h. This is consistent with previous data obtained from decidual
cells (18), but is more sustained than that in amniotic cells (17, 46).
Furthermore, a relatively low concentration of IL-1ß (0.1 ng/mL) gave
close to maximal stimulation of Cox-2 mRNA expression in our model,
which is consistent with earlier results obtained using amnion-derived
WISH cells (46), but 10-fold lower than that in decidual cells,
ECV cells, or human ovarian granulosa-luteal cells (18, 36, 48).
The effect of IL-1ß was not restricted to the lower segment
myometrium or pregnancy, as a similar response was obtained using
myometrial cells that originated from the fundal part of the
nonpregnant uterus. Furthermore, Cox-2 expression was elevated by
TNF and PMA in the myometrial cells that originated from either the
lower segment or the fundal part of the uterus, as is the case for
other pregnancy tissues (19, 49, 50, 51, 52). Previously, dexamethasone has
been shown to both stimulate (53, 54) and inhibit (50, 55) Cox-2
expression in cells derived from the amnion. In cultured myometrial
cells, dexamethasone inhibited the effect of IL-1ß on Cox-2
expression. All this suggests that proinflammatory cytokines can
promote sustained and relatively potent induction of Cox-2 expression
in human myometrial cells. However, it is still unclear what role
cytokine-induced production of prostanoids plays in the lower segment
myometrium. The major prostanoid produced by these cells is
PGI2 (Refs. 21, 38, 39 and the present work),
which has been shown to relax the myometrium (31, 56). Deletion of
PGI2 receptor leads to increased thrombosis and
suppression of the inflammatory response in mice (57). Thus,
PGI2 could potentially reduce the contractile
activity of the lower segment, induce vasodilatation, and prevent
thromboembolic complications in the uteroplacental circulation (58).
However, it is tempting to speculate that PGI2
might promote inflammation at the onset of labor and thus promote
parturition. It was recently reported that high doses of oxytocin (100
nmol/L) induce 3- to 4-fold induction of expression of Cox-2 protein in
human myometrial cells (59). In our experiments oxytocin (0.4 nmol/L)
did not induce the expression of Cox-2 mRNA or stimulate the conversion
of arachidonic acid to prostanoids. This indicates that, although
patients in our in labor group received oxytocin infusion, oxytocin
alone cannot explain the 15-fold elevation of Cox-2 mRNA steady state
levels at the onset of labor. We cannot, however, exclude the
possibility that oxytocin contributes to the induction in an indirect
manner by inducing the release of cytokines or by promoting the
expression of their receptors.
Our data demonstrate that PGE2 receptor subtype EP2 is expressed in unstimulated myometrial cell cultures, and that IL-1ß induces the expression of EP4 receptor. Expression of FP and EP receptor transcripts can be induced by IL-1ß and/or PMA in human ovarian granulosa-luteal cells (48) (our unpublished data), and PMA increases EP4 receptor mRNA levels in human monocytoid cell lines and in a human B cell line, but down-regulates the message levels in human T cell lines (60). In our model, PMA did not modulate the expression of the EP4 transcript. Thus, regulation of prostanoid receptor expression seems to be dependent on the cell type. Previously, expression of myometrial PG receptors has been shown to be dependent on gestational age, and in early human pregnancy the contractile EP3 and FP receptors are down-regulated (33), whereas FP receptor expression increases during labor at term (34). Interestingly, EP3 receptor is more prominently expressed in the fundal part of the primate uterus, whereas the relaxatory EP2 and EP4 receptors dominate in the lower segment (61). As myometrial cells, in addition to PGI2, produce PGE2 (Refs. 21, 38, 39 and the present work), this further indicates that prostanoids produced by the lower segment myometrium would rather relax than contract this part of the uterus.
In conclusion, Cox-2 transcript levels are elevated at the onset of human labor in human myometrial smooth muscle cells. This increase in Cox-2 expression may depend on cytokines released during parturition. Finally, as expression of prostanoid receptors is also regulated in these cells, not only the production of prostanoids but also responsiveness to them, may be modulated.
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Acknowledgments |
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Footnotes |
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2 These authors contributed equally to this work and appear in
alphabetical order.
Received November 18, 1999.
Revised May 8, 2000.
Accepted May 24, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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S. Oger, C. Mehats, E. Dallot, F. Ferre, and M.-J. Leroy Interleukin-1{beta} Induces Phosphodiesterase 4B2 Expression in Human Myometrial Cells through a Prostaglandin E2- and Cyclic Adenosine 3',5'-Monophosphate-Dependent Pathway J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5524 - 5531. [Abstract] [Full Text] [PDF]
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 W. T. Gerthoffer and C. A. Singer Secretory Functions of Smooth Muscle: Cytokines and Growth Factors Mol. Interv., November 1, 2002; 2(7): 447 - 456. [Abstract] [Full Text] [PDF]
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 L. Koumas and R. P. Phipps Differential COX localization and PG release in Thy-1+ and Thy-1- human female reproductive tract fibroblasts Am J Physiol Cell Physiol, August 1, 2002; 283(2): C599 - C608. [Abstract] [Full Text] [PDF]
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D. M. Slater, S. Zervou, and S. Thornton Prostaglandins and Prostanoid Receptors in Human Pregnancy and Parturition Reproductive Sciences, May 1, 2002; 9(3): 118 - 124. [Abstract] [PDF]
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G. C.S. Smith, W. X. Wu, and P. W. Nathanielsz Lipoxygenase gene expression in baboon intrauterine tissues in late pregnancy and parturition Mol. Hum. Reprod., June 1, 2001; 7(6): 587 - 594. [Abstract] [Full Text] [PDF]
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