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Department of Obstetrics and Gynecology, University of Illinois (J.J.K., A.T.F.), Chicago, Illinois 60612; the Departments of Molecular and Integrative Physiology (J.W., S.K.Da., S.K.De.) and Obstetrics and Gynecology (S.K.Da.), University of Kansas Medical Center, Kansas City, Kansas 66160; and Institute for Primate Research (C.B.), Nairobi, Kenya
Address all correspondence and requests for reprints to: Dr. A. T. Fazleabas, Department of Obstetrics and Gynecology, University of Illinois, 820 S Wood Street, M/C 808, Chicago, Illinois 60612. E-mail: asgi{at}uic.edu
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, and thromboxane A. The type of PGs produced varies
depending on the downstream enzymatic machinery present in a particular
cell type (2). Although COX-1 is expressed constitutively in a wide
range of tissues, COX-2 is inducible by tumor promoters, growth
factors, and cytokines. The COX enzymes have been extensively studied
in different cell types, tissues, and species, and it is now thought
that eicosanoids produced by COX-1 are important for the housekeeping
functions, whereas those produced by COX-2 lead to various pathological
changes in body tissues (2, 3). The endometrium undergoes striking morphological changes during the menstrual cycle and pregnancy. Under the influence of hormones and the developing embryo, changes in the local synthesis and metabolism of a variety of bioactive substances occur. Among these are PGs, which are potent biological mediators that act locally. They are considered to be proinflammatory and have been implicated in such mechanisms as ovulation (4, 5), menstruation (6), implantation (7, 8), and decidualization (8, 9, 10). The endometrium produces varying levels of PGs during the menstrual cycle and in pregnancy. In women, endometrial PG production is higher in the luteal phase and during menstruation than in the follicular phase (6, 11). In the rodent, PGs are implicated as important mediators of endometrial vascular permeability, which is evident at the site of implantation (9, 12). In ruminants, PGs of uterine origin are actively involved in luteolysis (13).
It is apparent that PGs are important mediators for the establishment of successful pregnancy in different species. Despite the extensive studies reported on COX expression, regulation, and potential function in the reproductive processes of other species, relatively little is known about COX expression and regulation in the primate uterus. Our laboratory focuses on delineating the events involved with maternal recognition of pregnancy, implantation, and establishment of pregnancy in the primate. In this report, we demonstrate the in vivo expression and localization of COX-1 and COX-2 in the baboon (Papio anubis) endometrium throughout the menstrual cycle and pregnancy.
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RT-PCR
Tissue was homogenized in TriReagent (Molecular Research Center, Inc., Cincinnati, OH), and RNA was extracted using the
protocol provided by the manufacturer. Aliquots of total RNA isolated
from baboon tissues were treated with 1 U/µl deoxyribonuclease
(Promega Corp., Madison, WI). RT was then performed in a
final volume of 20 µl with 1 µg RNA and 50 U/µl murine leukemia
virus reverse transcriptase at 42 C for 30 min. PCR
amplification was performed with the RT product, the appropriate
primers (50 pmol/tube), 0.5 µl 5 U/ml Taq polymerase
(Life Technologies, Grand Island, NY), and 0.25 µl 10
mCi/ml [-32P]deoxy-CTP. After an initial incubation at
94 C for 10 min, 32 amplification cycles consisting of 94 C (1 min), 55
C (1 min), and 72 C (2 min) were performed followed by 15 min of final
extension at 72 C. A linear curve was plotted using the number of
cycles of amplification vs. the densitometric values of the
PCR products, measured with a PhosphorImager (Molecular Dynamics, Inc., Sunnyvale, CA). The optimal number of cycles for
amplification that fit within the linear range was chosen for each set
of primers. Primers for COX-1 (sense, TCC AAC CTT ATC CCC AGT C;
antisense, CAT GGC AAT GCG GTT GC) or COX-2 (sense, TCC AGA TCA CAT TTG
ATT GAC A; antisense, TCT TTG ACT GTG GGA GGA TAC A) and H3.3
(described in Ref. 16) were added together in a single tube so that
amplification of the complementary DNAs for H3.3 and COX-1 or COX-2
occurred in the same tube. The PCR products were electrophoresed in
1.5% agarose gels, and the gels were dried and exposed to film.
Densitometric analysis of the PCR products was performed using a
PhosphorImager system. The densitometric values were normalized to
H3.3, which was coamplified as an internal standard (16). The
specificities of the PCR products for COX-1 and COX-2 were verified by
Southern hybridization. A specific oligonucleotide sequence within the
gene product derived from PCR was end labeled with
[
-32P]ATP. The unlabeled COX-1 and COX-2 PCR products
were electrophoresed on a 1.5% agarose gel and hybridized with the
[-32P]ATP-labeled internal oligonucleotide. The
authenticity of the PCR products was verified after exposure to film at
-80 C.
Immunocytochemistry
Immunolocalization of COX-2 was performed in Bouin’s fixed
paraffin-embedded sections using a Zymed-Histostain-SP kit (Zymed Laboratories, Inc., San Francisco, CA) (7, 8). The polyclonal
antipeptide COX-2 antibody (corresponding to amino acids 563–577) was
generated against the highly conserved C-terminal region of this
molecule (7, 8). The antibody was used at a concentration of 5 µg/ml.
Mouse implantation sites (day 5) were used as positive controls, and
negative controls consisted of preimmune serum at the same
concentration as the immune serum.
In situ hybridization
In situ hybridization was performed as described in
Das et al. (17). Frozen sections of tissue were mounted onto
poly-L-lysine-coated slides and stored at -70 C until
used. After removal from -70 C, the slides with the uterine sections
were placed on a slide warmer (37 C) for 2 min and then fixed in 4%
paraformaldehyde in PBS for 15 min at 4 C. After prehybridization,
uterine sections were hybridized to 35S-labeled sense or
antisense complementary RNA probes specific for mouse COX-1 and human
COX-2 for 4 h at 45 C. After hybridization and washing, the slides
were incubated with ribonuclease A (20 µg/ml) at 37 C for 15 min.
Ribonuclease A-resistant hybrids were detected after 1–3 weeks of
autoradiography using Kodak NTB-2 liquid emulsion (Eastman Kodak Co., Rochester, NY). The slides were poststained with
hematoxylin and eosin.
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). Although COX-1 was
faintly detectable in the late follicular phase tissue (Fig. 1A, lane
1), its expression increased during the luteal phase of the menstrual
cycle (Fig. 1A, lanes 2–4). After the establishment of pregnancy, the
signal for COX-1 was relatively weak compared with that of the luteal
phase tissues (Fig. 1A, lanes 5–8). The corresponding histogram, which
shows the mean densitometric values from two animals normalized to the
internal standard H3.3, also demonstrated a similar pattern of
expression. COX-2 mRNA expression in endometrial tissues, as determined
by RT-PCR, appeared to be uniform throughout the menstrual cycle and
early pregnancy (Fig. 1B). However, in near-term decidua, COX-2
expression was much lower compared with that in endometrial tissues at
other stages of the cycle and pregnancy. The densitometric analysis
from two animals shown in the corresponding histogram demonstrated a
similar pattern of expression.
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, lane 1), litle or no COX-1 was
detected in the endometrium of antiprogestin-treated animals (Fig. 2A, lane 2). Alternatively, COX-2 was expressed in the endometrium of both
the control (day 10 PO; Fig. 2B, lane 1) and the antiprogestin-treated
animals (Fig. 2B, lane 2).
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, A and B). The stromal cells were negative for COX-1. COX-2 was also
expressed in the lumenal epithelium of day 5 PO tissue (Fig. 3C), but
the signals in the glands were less intense and not as dramatic as
those of COX-1 (Fig. 3D). Stromal cells were also negative for COX-2.
No hybridization signals were evident when sense probes were used for
either COX-1 or COX-2.
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)
compared with the normally cycling day 10 PO controls (Fig. 4A). COX-2
hybridization was localized to the stromal cells in the endometrium of
antiprogestin-treated animals, whereas the lumenal and glandular
epithelia were negative (Fig. 4D). Endometrium from control animals on
day 10 PO also exhibited hybridization for COX-2 primarily in the
lumenal epithelium, but not in the glandular epithelium (Fig. 3
, C and
D, and Fig. 4C).
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). Very
faint expression was observed in some of the glands. COX-2 expression
again differed from COX-1 expression in early pregnant tissues. At the
nonimplantation site, a positive signal for COX-2 mRNA was observed in
lumenal epithelium (Fig. 5B), whereas glandular epithelium remained
negative. COX-1 mRNA expression was absent at the implantation site
(Fig. 5C), whereas COX-2 mRNA expression was intense and localized
specifically in the decidualizing cells of the maternal tissue (Fig. 5D). Other regions were negative for COX-2 mRNA. The pattern of
immunostaining for COX-2 protein was identical to that of the mRNA.
Lumenal epithelium stained positively for COX-2 protein at the
nonimplantation site (Fig. 6B), whereas
decidualizing cells in maternal tissue at the implantation site stained
positively for COX-2 protein (Fig. 6A). Near-term decidua displayed no
hybridization for either COX-1 or COX-2 mRNA (data not shown).
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COX has been detected in the endometrium of different species even before the identification of COX-2 as a unique gene product. In the human endometrium, strong positive staining for COX was observed on the surface epithelium, with rather weak immunoreactivity on the glands and no staining on the stromal cells (18). Rees et al. (19) demonstrated staining of COX in surface and glandular epithelium, specifically in luteal phase human endometrium. No staining was observed at any time in the cycle in the endometrial stroma or in first trimester pregnant tissues or decidua. Finally, Shaw et al. (20) demonstrated much greater COX-1 gene expression in the endometrium than in the decidua. In this study, we have shown similar expression patterns for COX-1 in the baboon endometrium and demonstrated that the localization was restricted to epithelial cells and was most prominent in luteal phase tissues. Furthermore, COX expression was higher in endometrium than in near-term decidua.
It is generally believed that COX-1 is ubiquitously expressed whereas COX-2 is induced by mitogens and cytokines. However, it is evident from this study and others that COX-1 is also specifically regulated in the uterus. Bany et al. (21) demonstrated an increase in both COX-1 and COX-2 expression in response to epidermal growth factor in rat endometrial stromal cells. Vascular endothelial growth factor induces COX-1, but not COX-2, expression in both human and bovine endothelial cells (22). In the periimplantation mouse uterus, the COX-1 gene was expressed in the uterine epithelium during the preimplantation period until the initiation of attachment, after which time the expression was down-regulated (7). In our study, COX-1 expression in epithelial cells of the endometrium was up-regulated during the luteal phase and was down-regulated with the establishment of pregnancy. Moreover, the absence of COX-1 expression in antiprogestin-treated animals observed in this study strongly implicates a role for progesterone in its induction. These data are consistent with observations in the mouse uterus (7). Treatment with antiprogestins during the luteal phase prevents the down-regulation of the progesterone receptor and inhibits the normal differentiation process in the baboon endometrium during the secretory phase (15, 23). Thus, it is conceivable that the inhibition of progesterone action with the antiprogestin at the time of ovulation prevents the expected induction of COX-1 during the luteal phase. The loss of COX-1 expression during pregnancy may also be associated with the total down-regulation of the progesterone receptor in all uterine epithelial cells (24).
Although COX-1 homozygous mutant female mice demonstrated apparently normal reproductive and developmental events with some defects in parturition (8, 25), COX-2-deficient mice demonstrated defects in ovulation, fertilization, implantation, and decidualization (8). In the mouse, the COX-2 gene is expressed in the lumenal epithelium and subepithelial stromal cells at the time of the blastocyst attachment reaction (7). Treatment of ovariectomized mice with progesterone and/or estradiol failed to induce uterine COX-2 mRNA, suggesting that perhaps this gene is not inducible by ovarian steroids in the mouse uterus. We have also observed the distinct expression of COX-2 specifically at the implantation site in the baboon, primarily in the decidualizing stromal cells of the endometrium. The increased expression of COX-2 may be due to the presence and/or secretion of cytokines by the uterus and the implanting embryo (26). Interleukins, produced by both the endometrium and the embryo (26), are well known inducers of COX-2. CG, which is expressed in large quantities by the embryo, has been shown to up-regulate COX-2 gene expression in human endometrial stromal cells (27). Although the factors and events associated with COX-2 expression at the implantation site remain unclear, it is apparent that the embryo is what triggers the cascade of events leading to the expression of this enzyme specifically in decidual cells at the site of implantation.
It has been suggested that the distinct roles that COX-1 and -2 play in
reproductive processes are due to differential subcellular sites of PG
production induced by these enzymes. Although COX-1 and -2 are both
membrane bound, COX-1 is present primarily in the endoplasmic
reticulum, and COX-2 is present in both the endoplasmic reticulum and
the perinuclear envelope (28). Lim et al. (8) demonstrated
distinct perinuclear localization of COX-2 in endometrial cells
exclusively surrounding the implanting blastocysts. It has been shown
that eicosanoids can mediate transcription by activating the nuclear
hormone receptor peroxisome proliferator-activated receptors
(i.e. PPAR, PPAR, and PPAR
) (29, 30). Thus, PGs
synthesized by COX-2 localized on the nuclear membrane can subsequently
act on nuclear receptors and regulate the transcription of essential
genes.
In summary, the differences in COX-1 and COX-2 expression in specific cell types during the menstrual cycle and pregnancy suggest an important role for these enzymes in the primate uterus. Although COX-1 induction in epithelial cells is most likely influenced by the action of progesterone, COX-2 induction in surface epithelium and decidualizing stromal cells at the implantation site may involve factors other than ovarian steroids, such as cytokines and other proinflammatory mediators. The dilation of microvessels and increased capillary permeability observed during the luteal phase at the time of endometrial receptivity may involve PGs produced via COX-1 (31). COX-2, on the other hand, may be important in promoting decidualization of stromal cells during pregnancy.
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Acknowledgments |
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Footnotes |
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2 These authors contributed equally to this work.
Received August 13, 1998.
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and . Proc Natl Acad
Sci USA 94:4312–4317 and . Proc Natl Acad Sci USA 94:4318–4323This article has been cited by other articles:
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