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Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University (K.T., Y.S., A.Iw., A.Ic.), Kyoto 606-8501; and the Department of Biochemistry, University of Tokushima School of Medicine (K.Y., S.Y.), Tokushima 770-8503, Japan
Address all correspondence and requests for reprints to: Atsushi Ichikawa, Ph.D., Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: aichikaw{at}pharm.kyoto-u.ac.jp
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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, are produced and released in uterine
tissues during parturition (8). As both PGE2 and
PGF2 have potent uterotonic activity (9),
these PGs have been thought to play roles in the physiological
parturition process. However, the specific roles these PGs play in
parturition remain unclear.
The actions of PGs are mediated by specific receptors on the surface of
cells (10). To examine the physiological roles of the PGF receptor (FP)
in parturition, we generated FP-deficient
(FP-/-) mice (11). As reported previously,
FP-/- mice are unable to deliver normal fetuses
at term, although they are normal in other aspects of reproduction
physiology. These mice did not show the normal decline of serum
progesterone levels that precedes parturition. Ovariectomy on day 19 of
pregnancy permitted successful delivery in these
FP-/- mice, indicating that parturition is
initiated when PGF2 interacts with FP in the
ovary of pregnant mice, inducing luteolysis. It has just recently been
reported that COX-1-deficient mice also show phenotypes of delayed
parturition (12). This report stated that the significant increase in
uterine PGF2 production on day 19 was lost in
COX-1-deficient mice, and that the administration of
PGF2 restored successful parturition. Hence,
uterine induction of COX-1 before parturition appears important for
inducing luteolysis. On the other hand, a number of reports have shown
that a large amount of PG production and induction of COX-2 are
detected in uterine tissues during parturition (8, 13). In humans,
these events that occur in uterine tissues were found only during
natural parturition and not upon cesarean section (14). Thus, it is
likely that PGs produced by COX-2 take part in parturition through
their uterotonic activity. From these results we speculated that
uterine expression of the COX isozymes is regulated by different
mechanisms, and that COX-1 and COX-2 preferentially contribute to the
induction of luteolysis and myometrial contractility, respectively. To
examine this possibility, we used FP-/- mice,
because luteolysis is impaired in late pregnancy, and parturition can
be artificially initiated by ovariectomy treatment. Here we show the
uterine expression of COX-1 and COX-2 in FP-/-
mice during late pregnancy and during ovariectomy-induced parturition.
The results observed suggest that these two isozymes are regulated by
parturition signals in very different ways.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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), C57BL/6 mice were used (Japan SLC,
Inc., Hamamatsu, Japan). For the series of ovariectomy experiments,
FP-/- mice were anesthetized by ether and
bilaterally ovariectomized on day 19 of pregnancy. Ovariectomy-induced
parturition occurred about 20 h after the operation. Uterine horns
were isolated 12, 16, 20 (during parturition), or 36 h after
ovariectomy for Northern analysis and 20 h after ovariectomy for
in situ hybridization analysis.
FP-/- mice that were sham-operated or left
untreated served as controls.
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Northern blot analysis
Uterine horns were dissected, freed from the conceptuses
and placentas, immediately frozen in liquid N2,
and stored at -80 C until use. Total RNA was extracted from both
uterine horns derived from one animal by the acid guanidinium
thiocyanate-phenol-chloroform method (15). Total RNA (15 µg) was
separated by electrophoresis on a 1.5% agarose gel and transferred
onto a nylon membrane (Biodyne-A, Pall, Port Washington, NY).
Hybridization was performed with 32P-labeled
complementary DNA (cDNA) fragments specific for COX-1 (16), COX-2 (16)
(corresponding to the first 409 amino acids of the coding region), and
the oxytocin receptor (OTR) (11) at 65 C in 6 x SSC (1 x
SSC is composed of 0.15 M NaCl and 0.015 M
sodium citrate), 0.5% SDS, and 5 x Denhardt’s solution. After
hybridization, filters were washed at 65 C in 2 x SSC-1% SDS,
and the hybrids were detected by autoradiography. The filters were then
rehybridized with a 32P-labeled cDNA fragment
specific for glyceraldehyde-3-phosphate dehydrogenase (GAPDH;
CLONTECH Laboratories, Inc., Palo Alto, CA).
Autoradiograms were subjected to densitometric analyses for
quantification of COX-1, COX-2, or OTR mRNA levels relative to GAPDH
mRNA levels using NIH Image software. For each group of tissues, three
animals were analyzed, and data were expressed as the mean ±
SEM.
In situ hybridization
In situ hybridization was carried out as described
previously (17). Uterine horns, dissected and freed from the fetuses
and placentas (for Fig. 5) or containing the fetuses and placentas (for
Fig. 6) were immediately frozen. Sections 10 µm in thickness were cut
on a Jung Frigocut 3000E cryostat (Leica Instruments, Nussloch,
Germany) and thaw-mounted onto
poly-L-lysine-coated glass slides. Antisense
riboprobes were synthesized by transcription with T3 RNA polymerase
(Stratagene, La Jolla, CA) in the presence of
[-35S]CTP for in situ
hybridization. The sections were fixed with 4% formalin and acetylated
with 0.25% acetic anhydride. Hybridization was carried out in a buffer
containing 50% formamide, 2 x SSC, 10 mM
Tris(hydroxymethyl)aminomethane (Tris)-Cl (pH 7.5), 1 x
Denhardt’s solution, 10% dextran sulfate, 0.2% SDS, 100
mM dithiothreitol, 500 µg/ml sheared single
stranded salmon sperm DNA, and 250 µg/ml yeast transfer RNA. The
riboprobes were added to the hybridization buffer at 1.5 x
105 cpm/µl. After incubation at 60 C for 5
h, the slides were washed for 1 h in 2 x SSC. The sections
were treated with 20 µg/ml ribonuclease A, followed by an additional
wash in 0.1 x SSC at 60 C for 1 h. The slides were then
dipped in nuclear track emulsion (NTB3, Eastman Kodak Co.,
Rochester, NY). After exposure for 5 weeks at 4 C, the dipped slides
were developed, fixed, and counterstained with hematoxylin and eosin.
The specificity of the signals for each probe was verified by their
disappearance when the sense probe was hybridized (see examples in Fig. 5j for COX-2 and Fig. 5k for COX-1, not shown for others) or an excess
amount of unlabeled probe was added (data not shown). These experiments
were repeated two or three times with different animals, and similar
results were obtained.
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The specificity of the signals in the immunohistochemical analyses was
confirmed by their disappearance when 1) the primary antibody was
preabsorbed by antigen (Santa Cruz Biotechnology, Inc.;
Fig. 7d), or 2) the sections were incubated with normal goat serum
instead of the primary antibody (data not shown). These experiments
were repeated two or three times with different animals, and similar
results were obtained.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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). The
major COX-2 transcript was detected as a 4.1-kb band. COX-2 mRNA was
hardly detected on days 12, 15, and 17 of pregnancy, but was markedly
induced during parturition on day 20; the mRNA level increased by
29.5-fold from that on day 17 (P < 0.01). Thereafter,
COX-2 mRNA levels gradually decreased between days 2 and 4 postpartum.
Hence, expression of COX-2 mRNA was highly induced during parturition.
In contrast, COX-1 mRNA was expressed during an earlier period of
pregnancy. COX-1 mRNA (the major transcript was 2.8 kb in size) was not
detectable on day 12, but the expression of COX-1 mRNA progressively
increased between days 15 and 17, reaching maximal levels on day 17
(3.7-fold of that on day 15; P < 0.05). By day 20,
during parturition, expression of COX-1 mRNA had decreased greatly
(P < 0.05), resulting in low levels being detected on
days 2 and 4 postpartum. Hence, the uterine expression of COX-2 mRNA
appeared to be closely associated with parturition, whereas the
expression of COX-1 mRNA occurred much earlier than this process.
Expression of COX-1, COX-2, and OTR mRNA in late pregnancy and
parturition in FP-/- mice
As reported previously (11), whereas the plasma concentration of
progesterone of wild-type mice decreased rapidly in late pregnancy,
FP-/- mice did not show such a decrease (Fig. 2). Plasma estradiol levels rose on day 19,
compared with those on day 17, in both wild-type and
FP-/- mice (P < 0.05) and were
not significantly different between the two types of mice during this
period (for days 17, 19, 21, and 22, P = 0.65, 0.91,
0.16, and 0.60, respectively). Therefore, in wild-type mice, the
calculated estradiol/progesterone ratio markedly increased on days 19
and 21, whereas it remained constant up to day 22 in
FP-/- mice.
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). COX-2 mRNA was highly induced during
parturition on day 20 in wild-type mice (to levels >20-fold of the
level on day 17). In FP-/- mice, however, no
such induction of COX-2 mRNA was found on day 20. In wild-type mice,
COX-1 mRNA was seen to decrease during parturition on day 20. In
contrast, no such decrease in COX-1 mRNA was found on day 20 in
FP-/- mice. As ovariectomy of
FP-/- mice on day 19 of pregnancy has been
shown to result in the successful delivery of fetuses 20 h after
treatment (11), we examined the mRNA expression of COX-1 and COX-2
compared with that of the OTR, a key factor in parturition, during
ovariectomy-induced parturition in FP-/- mice
(Fig. 4). OTR mRNA was markedly induced by
12 h after ovariectomy, began to decrease by 16 h
(P < 0.05), and became minimal at 36 h after
treatment (Fig. 4c). In contrast, expression of COX-2 mRNA
progressively increased, reached maximal expression at 20 h after
ovariectomy (during parturition), and decreased again by 36 h
(P < 0.05; Fig. 4a). Sham-operated or untreated mice
did not show such an induction of either OTR or COX-2 mRNA. Expression
of COX-1 mRNA decreased significantly by 16 h and was minimal by
36 h after ovariectomy (Fig. 4b). Sham-operated or untreated mice
did not show such a decrease. Thus, ovariectomy resulted in the mRNA
expression of COX-1 very different from that of COX-2 and OTR in these
FP-/- mice.
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). As this band was also
detected upon Northern analysis with another fragment of the coding
region as well as the 3'-untranslated region of COX-2 cDNA, but not
with an intron sequence as a probe (data not shown), the band is
probably one of the mature COX-2 gene products. In addition,
amplification of the full-length coding sequence of COX-2 mRNA by
RT-PCR in this sample resulted in a single band with the predicted size
(data not shown), suggesting that the higher band is presumably one of
the different COX-2 mRNA variants in the region other than the
coding sequence.
Cellular localization of COX-1 and COX-2 in uterine tissues of
FP-/- mice
Distribution of COX-1 and COX-2 mRNA was examined in uterine
tissues isolated from wild-type and FP-/- mice
throughout late pregnancy and parturition. The distribution of COX-1
and COX-2 in uterine tissues isolated from
FP-/- mice on days 15 and 17 of pregnancy was
identical to that in wild-type mice. The results obtained by in
situ hybridization analysis of COX-1 and COX-2 mRNA are summarized
in Table 1.
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and 6). Strong hybridization signals for COX-2
mRNA were observed in the circular layer of the myometrium in wild-type
mice (Fig. 5b). Hybridization was not observed in nontreated
FP-/- mice (Fig. 5e), but was again observed in
ovariectomized FP-/- mice (Fig. 5h). In
contrast, hybridization signals could not be detected for COX-1 mRNA in
the circular myometrium in wild-type or ovariectomized
FP-/- mice (Fig. 5, c and i), but COX-1 signals
were observed in nontreated FP-/- mice (Fig. 5f). COX-1 signals were detected in the endometrial epithelium in every
group, but extremely high endometrial epithelial expression of COX-1
was detected in FP-/- mice (Fig. 5, c, f, and
i). No hybridization signals were observed when sense probes of COX-2
and COX-1 were used as controls (Fig. 5, j and k, for control of b and
c, respectively; not shown for others). In all three groups of mice,
signals for both COX-1 and COX-2 mRNA were detected in the decidua and
the placental labyrinth (Fig. 6). COX-1 and COX-2 distribution in
sham-operated FP-/- mice was identical with
that in nontreated FP-/- mice (data not shown).
Thus, on day 20 of pregnancy, the uterine localization of COX-1 and
COX-2 mRNA in FP-/- mice was quite different
from that in wild-type mice. However, the uterine expression of COX-1
and COX-2 in ovariectomized FP-/- mice was
identical to that in wild-type mice.
Northern blot and in situ hybridization analyses
demonstrated that COX-2 expression in the myometrium is closely
associated with the occurrence of parturition. To confirm this
expression at the protein level, COX-2 expression was determined by
immunohistochemistry (Fig. 7). Intense
positive signals for the anti-COX-2 antibody were detected in the
circular myometrium in wild-type and ovariectomized
FP-/- mice, both of which underwent
parturition. In contrast, no signals were found in nontreated
FP-/- mice. When primary antibodies preabsorbed
by antigens were used, all signals were abolished.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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plays a crucial role in the induction of
parturition. Based on endocrinological analyses, luteolytic
PGF2 is thought to be derived from
intrauterine tissues. It was recently reported that COX-1-deficient
female mice have a defect similar to that of
FP-/- mice, which can be restored by the
administration of PGF2 (12). This study also
showed a lack of PGF2 synthesis from
intrauterine tissues during late pregnancy in COX-1-deficient mice. It
is therefore likely that PGF2 synthesized by
COX-1 in intrauterine tissues plays a crucial role in the induction of
luteolysis.
In wild-type female mice, COX-1 mRNA was induced on day 15, reached
peak levels on day 17, and decreased on day 20 when parturition
occurred. On day 17, COX-1 mRNA was highly expressed in the epithelial
layer of the endometrium and the circular layer of the myometrium, but
COX-1 expression in endometrial epithelial cells decreased and that in
myometrial cells disappeared on day 20, during parturition. These
results agreed with previous reports using COX-1-specific antibodies
(20). In FP-/- mice, high levels of COX-1 mRNA
expression were also observed on day 17, but unlike in wild-type mice,
this expression was still high on day 20. In these mice, COX-1 mRNA was
persistently expressed in both the endometrial epithelium and the
myometrium on day 20, as shown by in situ hybridization. In
ovariectomized FP-/- mice, COX-1 mRNA
expression began to decrease by 16 h after ovariectomy and reached
minimal levels by 36 h, as observed on day 20 in wild-type mice.
As the failure of parturition in FP-/- mice is
due to incomplete luteolysis, the persistent expression of COX-1 mRNA
in endometrial epithelial and myometrial cells may reflect the result
of a persistent production of progesterone in
FP-/- mice (11). Hence, progesterone can be
considered to be one of the possible positive regulators of COX-1
expression in these cells. Indeed, administration of progesterone was
sufficient to elicit persistent expression of COX-1 mRNA in
ovariectomized FP-/- mice (our
unpublished data). In this case, if this COX-1 expression is
responsible for luteolytic PGF2 synthesis,
progesterone withdrawal could serve as a negative feedback system of
uterine PG synthesis. On the other hand, COX-1 induction was observed
on day 15 in intrauterine tissues, which is later than the increase in
plasma progesterone. Some other additional regulators are probably
necessary for the induction of COX-1 gene expression.
COX-2 expression during parturition
In contrast to the abundant expression of COX-1 mRNA, expression
of COX-2 mRNA in intrauterine tissues was not as high throughout late
pregnancy. However, on day 20, COX-2 expression was highly induced in
the myometrium of wild-type females. One of the most remarkable
findings in this study is the absence of COX-2 expression in the
myometrium of FP-/- mice. As plasma estradiol
levels in FP-/- mice are comparable to those in
wild-type mice throughout pregnancy (Fig. 2), the absence of COX-2
expression on day 20 in FP-/- mice is the
result of a persistent production of progesterone. When these mice were
subjected to ovariectomy, COX-2 as well as OTR expressions were induced
in the myometrium (Fig. 5 and data not shown). Both COX-2 and OTR
expressions are known to be positively regulated by estradiol in
nonpregnant animals, but progesterone did not have an inhibitory effect
on the estradiol-induced expression of either gene (21, 22), suggesting
that induction of COX-2 and OTR is mediated by some factors downstream
of ovariectomy-induced progesterone withdrawal. However, OTR expression
reached maximal levels by 12 h after ovariectomy, whereas COX-2
expression was initiated by 16 h after treatment and was greatly
enhanced during parturition. Such a different profile of COX-2
induction indicates that the mechanisms underlying COX-2 expression are
different from those for OTR gene induction, and that the expression of
COX-2 in the myometrium is closely associated with the occurrence of
parturition. It has been shown that the in vivo and in
vitro production of PGs from uterine tissues is markedly elevated
by the stimulation of oxytocin or interleukin-1ß (IL-1ß) (13, 20, 23). The induction of OTR preceding COX-2 expression in the myometrium
suggested that COX-2 expression may be initiated by oxytocin signaling.
On the other hand, IL-1ß is also produced locally from immune cells
within uterine tissues; this is inhibited by progesterone (24, 25, 26).
Hence some cytokines are postulated to be potential signaling molecules
working during the onset of labor (27). Indeed, IL-1ß was shown to
induce prominent COX-2 expression at the transcriptional level in rat
myometrial cells (20). It is therefore likely that locally synthesized
cytokines such as IL-1ß initiate or enhance myometrial COX-2
expression during parturition. Alternatively, it is still possible that
the delivery of fetuses itself enhances myometrial COX-2
expression.
What is the role of uterine COX-2-derived PGs in parturition? As the
expression of COX-2 in the myometrium is closely associated with the
occurrence of parturition, COX-2-derived PGs seem to play a role in the
final pathway of parturition. The facts that PGE2
and PGF2 are the major products of uterine COX
and that both are known to have potent uterotonic actions (9) suggest
that COX-2-derived PGs may be responsible for myometrial contraction.
However, in FP-/- mice, ovariectomy can restore
parturition; hence, the uterotonic action of
PGF2 is dispensable for parturition (11).
Uterine PGE2 has also been thought to be involved
in cervical ripening (28). The roles of the uterotonic and
nonuterotonic actions of PGE2 should be addressed
using mice deficient in each of the subtypes of PGE receptors.
The present study indicates that uterine expression of the COX enzymes is biphasic during the periparturient period and is under the control of progesterone. Interestingly, down-regulation of COX-1 expression and induction of COX-2 were also found in human intrauterine tissues during labor (14, 29, 30), although the human circumstance is more complicated; ovarian progesterone production does not continue, luteolysis does not occur, and the systemic progesterone concentration does not decrease prepartum. A decrease in the local concentration of progesterone by alteration of its metabolism has been proposed as a possible mechanism underlying the onset of human labor (31), but it remains to be tested whether expression of the COX enzymes is regulated under the influence of progesterone or by different mechanisms. However, the association of COX-2 induction in intrauterine tissues with the occurrence of labor may reflect the importance of COX-2-derived PGs in the natural parturition process in humans.
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Acknowledgments |
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Footnotes |
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Received May 17, 1999.
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References |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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in
mid-pregnant rat uterus and at parturition. Prostaglandins Leukotrienes
Essent Fatty Acids 40:27–30[CrossRef][Medline]
in the
uterus during the second half of pregnancy in the mouse. Endocrinology 131:14–20This article has been cited by other articles:
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and *, P
< 0.05 vs. days 15 and 17, respectively). Northern blot
experiments were independently repeated three times with different
animals, and similar results were obtained. Representative results are
shown in the upper panels.
