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Laboratory of Pregnancy and Newborn Research, Physiology Department, Cornell University College of Veterinary Medicine, Ithaca, New York 14853
Address all correspondence and requests for reprints to: Peter W. Nathanielsz, M.D., Ph.D., Sc.D., Laboratory for Pregnancy and Newborn Research, Department of Physiology, T9 016 VRT, Cornell University College of Veterinary Medicine, Ithaca, New York 14853-6401. E-mail: pwn1{at}cornell.edu
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Abstract |
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Introduction |
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Regulation of PGHS-2 and PGHS-1 has been extensively studied. A series of PGHS-2 inducers has been identified, e.g.lipopolysaccharide (12), cAMP (13), interleukin-1 (14), tumor necrosis factor (15), transforming growth factor-ß (16), phorbol ester (17), hCG (18), endothelin (16), and glucocorticoids (19). Unfortunately, most studies have been conducted in in vitro cell culture systems. Such paradigms do not reflect the totality of events present in the intact structure of the tissue; in particular, in vitro studies do not reflect local or blood-borne in vivo cell to cell communication. Therefore, they cannot completely reproduce the physiological response of the cells as in vivo. A few studies have characterized in vivo regulation of PGHS-2 in rat ovary (8, 18); however, no studies have examined PGHS regulation in uterine tissues in vivo. Intrauterine PG production plays a critical role in many reproductive processes.
Increased PG production within the uterus plays a central role in the initiation and maintenance of labor by regulating cervical ripening and myometrial contractility in several species, including sheep (20). The intrauterine tissues are the principal sources of PG involved in the paracrine regulation of labor (21). The level of PGHS-2 messenger RNA (mRNA) rises after the onset of labor in human amnion and decidua (22, 23). We have recently demonstrated that PGHS-2 mRNA and protein levels increased dramatically in ovine myometrium and endometrium during both glucocorticoid-induced premature labor and spontaneous term labor (10). These findings suggest that the development of a critical concentration of PGHS-2 enzyme in intrauterine tissues is crucial to the promotion of labor. Characterization of PGHS regulation in uterine tissues is required to provide a clear understanding of the control of parturition.
In sheep, elevated plasma estrogen concentrations at the end of pregnancy (24) and a decrease in plasma progesterone (25) immediately before the onset of labor are the typical labor-associated hormone changes that precede an increase in PGHS-2 mRNA and protein levels in both myometrium and endometrium (10). Based on these observations, we hypothesized that in sheep, estradiol and progesterone are involved in regulating PGHS-2 production. In this study, we examined the in vivo effects of estradiol and progesterone on PGHS-1 and PGHS-2 expression at both mRNA and protein levels using a nonpregnant ovariectomized (OVX) sheep model. Immunocytochemical staining of PGHS was applied to sheep myometrium and endometrium to determine the differential distribution of PGHS-2 and PGHS-1 in ovine uterus.
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Materials and Methods |
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Tissues were removed while the ewe was under halothane general anesthesia. Myometrium and caruncular and intercaruncular endometria were rapidly dissected and frozen in liquid nitrogen for later RNA and protein extractions. Frozen tissues were stored at -80 C until extracted for RNA and proteins. Another similar portion of the myometrium and endometrium was fixed in 4% paraformaldehyde for 24 h at room temperature for later immunocytochemical analysis.
Total RNA preparation and Northern blot analysis
Total RNA was prepared from individual tissues as previously
described (27). Briefly, total RNA was isolated from the myometrium and
the well mixed caruncular and intercaruncular endometria by
homogenization in 4.2 M guanidinium thiocyanate solution.
RNA was pelted through a 5.7-M cesium chloride cushion. The
RNA purity and recovery of each tissue were determined by UV
spectrophotometer (260 and 280 nM). There were no
differences in the yield of RNA per mg tissue between ewes with or
without different steroid treatments. Purified RNA was resuspended in 1
mM EDTA and stored at -80 C.
Samples of total RNA (40 µg/lane) from each tissue were denatured in 17.4% (vol/vol) formaldehyde, 50% (vol/vol) formamide, 20 mM MOPS (3-(N-morpholino)propanesulfonic acid), 5 mM sodium acetate, and 1 mM EDTA, pH 7.0, for 5 min at 65 C and separated on a 1% (wt/vol) agarose-0.66 M formaldehyde gel. Ethidium bromide-stained ribosomal RNA bands were visualized (UV) to ensure that RNA degradation had not occurred and an equal amount of RNA has been loaded into each lane. After electrophoresis, RNA was transferred to a nylon membrane (GeneScreen Plus, New England Nuclear-DuPont, Wilmington, DE) by capillary blotting for 24 h in 10 x SSC (1 x SSC is 0.15 M NaCl and 0.015 M sodium citrate, pH 7.0). Completion and uniformity of transfer were assessed by determining transfer of 28S and 18S ribosomal RNA from the gel. Membranes were prehybridized at 42 C for 5 h in hybridization solution [50% (vol/vol) deionized formamide, 50 mM sodium phosphate, 0.8 M NaCl, 2% (wt/v) SDS, 100 µg salmon sperm DNA/ml, 20 µg transfer RNA/ml, and 1 x Denhardt’s solution (1 x = 1% solution of BSA, Ficoll, and polyvinylpyrrolidone).
Recombinant human PGHS-2 and ovine PGHS-1 complementary DNAs (cDNAs)
were purchased from Oxford Biomedical Research (Oxford, MI; catalogue
no. R91-PGHS-2 and R74-PGHS-1). PGHS-2 and PGHS-1 cDNA probes were
labeled with [
-32P]deoxy-CTP using the random priming
method (New England Nuclear-DuPont) to specific activities of
approximately 1 x 109 cpm/µg and used at a final
concentration of 1 x 106 cpm specific probe/ml
hybridization solution.
Hybridization was carried out at 42 C for 20 h in hybridization solution containing the specific PGHS-1 or PGHS-2 cDNA probe. Membranes were washed sequentially in 2 x SSC at room temperature for 10 min and in 0.5 x SSC with 0.1% SDS at 65 C for 30 min. Kodak X-Omat AR film was exposed to the membrane with intensifying screens at -80 C. Exposure durations were varied to achieve hybridization signals within the limited linear range for densitometry (2–7 days).
Membranes were stripped of PGHS-2 or PGHS-1 probes by boiling in
0.1 x SSC with 0.1% (wt/vol) SDS for 30 min and rehybridized
with [-32P]deoxy-CTP-labeled 18S cDNA probe to
normalize each mRNA level. Autoradiographed signals were quantified by
Scan densitometry (Biosoft, Cambridge, UK).
Solubilized cell membrane extraction and Western blot analysis
Solubilized cell membrane extracts from myometrium and
endometrium were prepared as described previously (10). The protein
concentration was determined by the method of Bradford (Bio-Rad
Laboratories, Richmond, CA). The solubilized proteins (100 µg/lane)
were then separated on 10% SDS-PAGE and electrophoretically
transferred to the nylon membrane (Imobilon, Millipore Corp., Bedford,
MA), using a Bio-Rad transfer blot cell. Western blot analysis was
performed as previously described (10). The protein bands were
visualized using an enhanced chemiluminescence Western blotting
detection kit (ECL, Amersham Life Sciences, Arlington Heights, IL). The
molecular sizes of the proteins were determined by running standard mol
wt marker proteins (Bio-Rad) in an adjacent lane. Chemiluminescence
signals were analyzed and quantified with the scanner, and data were
analyzed with a densitometry program-Scan analysis and quantified
against an arbitrary scale in the plot.
Antibodies for PGHS-2 and PGHS-1 used for Western blot analysis
A mouse monoclonal antibody for ovine PGHS-1 purchased from
Oxford Biochemical Research (catalogue no. R71) was used at 1:100
dilution and incubated at 4 C for 20 h. A rabbit polyclonal
antibody for PGHS-2 raised against a synthetic peptide corresponding to
a distinct C-terminal region of human PGHS-2 (catalogue no. PG27,
Oxford Biomedical Research) was used at a 1:1000 dilution and incubated
at 4 C for 20 h. Normal mouse serum was used as a control serum
for PGHS-1 Western blot analysis, and normal rabbit serum was used as a
control serum for PGHS-2 under the same conditions as the primary
antibodies. A highly purified ovine PGHS-2 (Oxford Biomedical Research;
catalogue no. NP 04) was also used as a positive control for PGHS-2
Western blot analysis. Two different second antibodies, horseradish
peroxidase-conjugated sheep antimouse IgG (for PGHS-1) and horseradish
peroxidase-conjugated donkey antirabbit IgG (for PGHS-2), were
incubated with the membranes at room temperature for 1 h.
Immunocytochemistry for PGHS-2 and PGHS-1
Paraffin sections (4 µm) of ovine myometrial and endometrial
tissues were immunostained for PGHS-2 or PGHS-1 using the avidin-biotin
immunoperoxidase method. Briefly, sections were deparaffinized in
xylene and rehydrated in an ethanol series (100%, 80%, and 50%) and
deionized water. Unless otherwise specified, all slides were
sequentially incubated for various times at room temperature with each
of the following reagents: 1) 3% (vol/vol)
H2O2 in methanol for 30 min to block endogenous
peroxidase activity; 2) 0.1% (wt/vol) trypsin (Sigma Chemical Co., St.
Louis, MO) and 0.1% (wt/vol) CaCl2 in water at 37 C for 15
min; 3) 25% (vol/vol) normal goat or horse serum and 5% (wt/vol) BSA
in 0.05 M Tris-Cl with 0.15 M NaCl, pH 7.6, for
1 h; 4) rabbit antihuman PGHS-2 polyclonal serum (1:500 dilution)
or mouse antiovine PGHS-1 (1:100 dilution), as used for Western
blotting described above, for 20 h at 4 C; 5) biotinylated goat
antirabbit or horse antimouse IgG (Vector Laboratories, Burlingame, CA)
for 0.5 h; 6) avidin-biotin complex (Vector): 40 µl of each in 5
ml 0.05 M Tris-Cl, pH 7.6, for 0.5 h; and 7)
3,3-diaminobenzidine tetrahydrochloride (Sigma) for 10 min: 4 µg/10
ml 0.05 M Tris buffer, pH 7.6, to which was added 0.2 ml
3% H2O2. After each incubation, the slides
were washed with TBS for 15 min except for step (3). The slides were
then counterstained with hematoxylin and mounted in Permount (Fisher
Scientific, Fairlawn, NJ). The specificity of immunostaining for the
enzyme was confirmed by two approaches: 1) omission of the primary
antibody, and 2) incubation of the slides with normal rabbit or mouse
serum instead of the primary antibody.
Statistical analysis
One-way ANOVA was used to test for significant differences among
the four groups (i.e. C, E, P, and EP), followed by multiple
comparison using the Tukey-Kramer procedure. Data are presented as the
mean ± SEM
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In endometrium, PGHS-2 and
PGHS-1 mRNA levels were too low to be detected by Northern blot
analysis (data not shown).
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). In
contrast, in the endometrium, progesterone was a more potent stimulator
of PGHS-2 expression (Fig. 4;
P < 0.01). A significant increase in PGHS-2 protein in
the endometrium was also observed after estradiol or estradiol plus
progesterone treatment (Fig. 4; P < 0.05). The PGHS-1
protein level remained unchanged after any of the steroid treatment in
both myometrium and endometrium (P > 0.05; Figs. 5 and 6).
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). PGHS-2 was also localized in
myometrial smooth muscle cells (Fig. 7B). PGHS-1 was localized in
endometrial stromal cells and glandular epithelial cells (Fig. 7C) as
well as in smooth muscle cells of the myometrium (Fig. 7D). PGHS-1 was
also localized in the endothelial cells and the smooth muscle cells of
blood vessels (Fig. 7, E and F). Ovine endometrium stained in absence
of primary PGHS-2 (Fig. 7G) and PGHS-1 (Fig. 7H) antibodies, which were
replaced by normal rabbit or mouse serum. Immunostaining for PGHS-2 and
-1 was abolished.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Steroid-receptor complexes induce or repress the expression of genes by interacting with regulatory DNA sequences and transcription factor(s). The upstream promoter regions (up to 1.8 kilobases) of PGHS-2 genes from several species have been sequenced and were not reported to contain estradiol response elements (7, 31). However, the promoter for ovine PGHS-2 has not been cloned, and the potential regulators remain undetermined. Although high homology of the 5'-flanking region of PGHS-2 gene was found in the human, murine, and rat PGHS-2 promoter, dissimilarity was observed between the human and chicken PGHS-2 promoter sequences (7). In addition, the longest PGHS-2 promoter nucleotide sequence that currently has been cloned is about 1.8 kilobases. Further study of the PGHS-2 gene is necessary to prove or disprove the existence of an estrogen response element in the more distant end of PGHS-2 promoter or other sequence motifs associated with estrogen action.
The differential effect of progesterone on PGHS-2 expression in
myometrium and endometrium is a striking finding of the present
studies. Progesterone, either alone or combined with estradiol,
up-regulated PGHS-2 protein abundance in the endometrium, but not in
the myometrium. There has been much speculation over many years that
progesterone stimulates PGHS-2 expression and increases PG production
in ovine placenta between 0.6–0.7 gestation (32). Plasma progesterone
concentration (33) increases markedly between 0.6–0.7 of ovine
pregnancy, whereas the estrogen concentration is low as a result of
minimal placental 17-hydroxylase activity throughout the majority of
ovine pregnancy (34). High progesterone concentrations are temporally
associated with the development of PG production by the ovine placenta.
The activity of placental PGHS-2 increases markedly in the second half
of gestation, resulting in a progressive increase in the release of
PGE2 into the fetal circulation in late pregnancy (32). The
increased PG production may play a key role in the promotion of ovine
parturition, probably acting through several biochemical pathways. In
addition, an earlier study found the progesterone promoted PGF
production from nonpregnant ovine endometrium (35). However, it is not
clear what the molecular mechanism of progesterone is that regulates PG
production. Our findings provide firm, and the first, evidence to
support the hypothesis that progesterone-stimulated PG production in
late gestation in ovine uterine tissues is mediated through activating
PGHS-2 synthesis. However, it will be necessary to examine estradiol
and progesterone regulation of placental PGHS-2 expression in
vivo and in vitro around the critical time of ovine
pregnancy (
0.6 gestation of pregnancy).
It is of interest that progesterone regulation of PGHS-2 expression is strictly tissue specific. Similar tissue specificity has been observed for glucocorticoids and gonadotropin. Glucocorticoids stimulate PGHS-2 expression in cultured human amnion cells (19), but inhibit PGHS-2 expression in numerous other cell types (14). In addition, gonadotropin stimulates PGHS-2 expression in rat ovary (8, 18), but not in other tissues studied. These results indicate that cell type-specific subcellular signals are important to direct responses to steroid hormone regulation in some cell types, while leaving the PG synthetic activity of other cells unaltered. This form of differential regulation is of fundamental importance for PG synthesis, which appears ubiquitous, if not universal, in cell function.
In contrast to our findings, neither estradiol nor progesterone alters PGHS-2 expression in dispersed human amnion cells (19). The differences between our observations on steroid regulation of PGHS-2 expression may be the result of species- and/or tissue-specific differences. PGHS-2 mRNA and protein are present at barely detectable levels in sheep fetal membranes (10, 36) in contrast to abundant PGHS-2 expression in human amnion. Equally important is the need to evaluate differences between in vivo and in vitro approaches. In many ways in vivo approaches are more physiological and permit the evaluation of local cell-cell and systemic processes that occur throughout the body. These considerations are particularly important in several situations: when more than one hormone exerts a regulatory effect; when the effects of individual hormones are dose dependent, even potentially acting on different receptors at different concentrations; when interacting hormones have opposing effects, as in the case of estrogen and progesterone in reproductive tissue; and when the regulation is indirect (hormone metabolites or secondary regulators may function in vivo) and different cell types work together to complete the hormone response cascade. Thus, in vivo studies provide essential information to enable understanding of physiological regulation of PGHS expression.
The precise cellular localization of PGHS-1 and PGHS-2 in the sheep uterus was determined by immunocytochemistry. PGHS-2 was immunolocalized in myometrial cells and epithelial cells of endometrial glands. We have previously demonstrated that ER was localized in ovine myometrial cells and epithelial cells of endometrial glands by immunocytochemistry and in situ hybridization in a similar distribution of PGHS-2 (37). These findings support a direct control of estrogen in regulating PGHS synthesis in the ovine endometrium and myometrium.
Immunoreactive PGHS-1 was located in the myometrial cells, endothelial and smooth muscle cells of blood vessels, as well as epithelial cells of endometrial glands and stromal cells. The differential distribution of PGHS-1 and PGHS-2 is consistent with the differential function of both enzymes. The evidence we present supports the view that PGHS-1 is constitutively expressed in several cell types of the uterus, which makes it a candidate for a housekeeping gene. One of the important features of PGHS-1 is its localization in endothelial and smooth muscle cells of blood vessels, which is consistent with the findings of the previous report (38). Localization of PGHS-1 in blood vessels further supports the critical function of PGs in regulating blood flow and may also explain the unwanted side-effects, such as dysfunction of fetal ductus arteriosus, of those nonsteroid antiinflammatory drugs that are nonspecific inhibitors of both PGHS-1 and PGHS-2 when used for prevention of premature labor (39). The availability of specific PGHS-2 inhibitors would provide a useful focal point for pharmacological manipulation of preterm and postterm labor.
In conclusion, estradiol-dependent activation of PGHS-2 gene expression and active PGHS-2 synthesis accounts for the increased PGHS-2 level in sheep myometrium in vivo, in which progesterone did not have any effect on myometrial PGHS-2 expression. In contrast, progesterone is a more potent stimulator of endometrial PGHS-2 expression. Estradiol and progesterone did not regulate PGHS-1 expression in the ovine uterine tissues studied. The different distributions of PGHS-1 and -2 in myometrium and endometrium are consistent with the differential functions of both enzymes.
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Footnotes |
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2 Current address: J. A. Baker Institute for Animal Health,
Cornell University, Ithaca, New York 14853.
Received April 24, 1997.
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References |
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. J Biol Chem 267:10816–19822 output by cultures of epithelial and stromal cells
in human endometrium. J Steroid Biochem 24:297–301
-hydroxylase/C-17,20-lase,
aromatase and sulphatase in dexamethasone induced and natural
parturition. J Endocrinol 122:351–359
concentrations in uteri and plasma of ovariectomized ewes. J Endocrinol 73:427–439
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W. X. Wu, N. Unno, X. H. Ma, and P. W. Nathanielsz Inhibition of Prostaglandin Production by Nimesulide Is Accompanied by Changes in Expression of the Cassette of Uterine Labor-Related Genes in Pregnant Sheep Endocrinology, July 1, 1998; 139(7): 3096 - 3103. [Abstract] [Full Text] [PDF]
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