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a Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The effects of estrogen and P4 are mediated through their respective nuclear receptors, ER and PR. These receptors act as ligand-activated transcription factors that transduce steroidal signals into the specific changes in gene expression that give rise to uterine morphogenic responses [12, 13]. The essential role of ER and PR in mediating uterine responses to estrogen and P4 has recently been confirmed by null mutation of these genes in mice. Mice lacking functional ER (ER knock-out mice [ERKO]) display an inability to respond to the proliferative and inflammatory stimuli of estrogen [14, 15], while mice lacking PR (PRKO) display estrogen-dependent hyperplasia of the uterine epithelium, stromal hypocellularity, and significant uterine inflammation [9, 10].
Receptors for estrogen and P4 have been localized by in situ radiolabeled hormone binding or by immunohistochemistry to the epithelial, stromal, and myometrial compartments of the uterus in a number of species [16–19]. Consistent with the localization of ERs in stromal tissue, recent studies using stromal/epithelial tissue recombination between wild-type and ERKO tissues have demonstrated that the proliferative effects of estrogen in the uterine epithelial compartment are imparted by a paracrine action of ERs that reside in the stromal compartment [20]. The identification of stromal receptors as potential paracrine mediators of the epithelial proliferative responses to estrogen prompts a closer examination of the localization and regulation of ER and PR in the various mouse uterine compartments.
It is well established that the opposing actions of estrogen and P4 in the uterus result from an interdependent regulation of ER and PR expression [16, 19, 21, 22]. Studies on whole uteri of primates and cats have demonstrated that ER and PR expression is stimulated by estrogen, while P4 reduces levels of both receptors [23–25]. Previous studies in neonatal mice have indicated that the estrogen-induced increase in ER expression is accompanied by an increase in the number of ER-positive luminal epithelial cells while stromal ER expression is decreased [26]. Further, it has previously been reported that treatment of immature mice with estrogen results in decreased binding of [125I]progesterone to luminal epithelium while stromal binding of the hormone is increased [17]. These data suggest that estrogen has both positive and negative effects on the expression of PR in specific mouse uterine compartments. Although this dual regulatory effect of estrogen on PR has not been observed in some species, including primates and cats [16, 19], it is strongly supported by recent immunohistochemical studies carried out in adult rats [27] and may be specific to rodents.
While it is clear that the complex uterine responses to estrogen and P4 are in part mediated by differential cell-specific expression of ER and PR, details on how this expression is affected by hormonal treatment in the adult mouse are still lacking. To address this issue, we implemented an immunohistochemical approach to localize ER and PR in the mouse uterus and to examine their intercompartmental regulation by estrogen and P4 using a hormonal regimen known to elicit all of the functional responses that are mediated by ER and PR in the adult mouse [9]. To clearly differentiate between ER- and PR-dependent responses, we have exploited the PRKO mouse to delineate those responses due solely to ER. Finally, we have correlated receptor regulation with the uterine epithelial response to both receptors using lactoferrin (LF) as an epithelial secretory marker protein that is known to be regulated in a positive manner by estrogen and in a negative manner by P4 [28, 29].
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Polyclonal rabbit anti-ER antibody (cat. sc-542) was purchased from Santa Cruz Biotechnology (Santa Cruz, CA) and was used at a determined optimal dilution of 1:250 in 10% goat serum in PBS. Polyclonal rabbit anti-PR antibody (cat. A0098) was purchased from DAKO (Glostrup, Denmark) and was used at a determined optimal dilution of 1:100 in 10% goat serum in PBS. Polyclonal rabbit anti-LF antibody was acquired from Dr. Christina Teng (NIEHS, Research Triangle Park, North Carolina) and was used at a determined optimal dilution of 1:400 dilution in 10% goat serum in PBS. Biotinylated goat anti-rabbit IgG (cat. BA-1000) was purchased from Vector Laboratories (Burlingame, CA). Goat serum was purchased from Gibco BRL (Grand Island, NY) and heat inactivated at 56°C for 30 min before use. Diaminobenzidine (DAB) peroxidase substrate (Sigma Fast DAB Tablet Sets), P4, estradiol-17ß (E2), and sesame oil were purchased from Sigma Chemical Co. (St. Louis, MO). E2 was dissolved in ethanol, then diluted in sesame oil to a concentration of 20 ng/µl. P4 was dissolved directly in sesame oil at 55°C for 1 h at a concentration of 20 µg/µl. Histo-Clear was obtained from National Diagnostics (Atlanta, GA). Antigen Retrieval Citra was purchased from BioGenex (San Ramon, CA).
Animals
All mice were maintained in accordance with the NIH Guide for the Care and Use of Laboratory Animals. PRKO mice were generated in our laboratory as described previously [9]. Wild-type and PRKO mice were housed in the animal facility at Baylor College of Medicine (Houston, TX).
Hormone Treatments
Female wild-type and PRKO 8-wk-old mice were ovariectomized and then rested for 7 days. Mice were injected s.c. daily for 4 days with 50 µl of sesame oil containing no hormone, 1 µg E2, or 1 µg E2 + 1 mg P4. Three mice were included in each treatment group. Mice were killed 24 h after the final injection and uteri were isolated.
Immunohistochemistry
Uteri were fixed in Bouin's fixative at room temperature for 7 h, then washed in 70% ethanol at room temperature overnight. After fixation, the tissue was dehydrated in graded ethanol solutions, cleared in xylene, and embedded in paraffin for sectioning; 5-µm sections were cut and mounted on poly-L-lysine slides (Cel Tek Inc., Glenview, IL). Sections were deparaffinized in Histo-Clear and rehydrated in graded ethanol solutions. Peroxidase quenching was performed with 3% H2O2 in methanol for 10 min. For PR staining, sections were boiled in Antigen Retrieval Citra for 10 min in a microwave oven and then washed in PBS [30]. All subsequent steps were carried out at room temperature. Sections were blocked with 10% goat serum in PBS for 30 min, followed by incubation with the primary antibody for 4 h. Sections were incubated without primary antibody or with nonimmune rabbit serum as a control. Sections were then washed in PBS for 20 min followed by incubation with the biotinylated secondary antibody for 1 h. After a 10-min wash in PBS, sections were incubated for 30 min with streptavidin-conjugated peroxidase diluted 1:500 in PBS for 30 min. After a 10-min wash in PBS, the localization of the primary antibody was visualized with the imidazole-DAB reaction for 3–10 min, producing a brown-colored stain. Sections were then counterstained in hematoxylin, dehydrated through graded ethanol solutions, cleared in xylene, and mounted with Permount (Fisher Scientific, Pittsburgh, PA) for brightfield microscopy. Images were acquired digitally using a Zeiss Axioskop microscope (Carl Zeiss Inc., Thornwood, NY) coupled with a Hamamatsu C5810 CCD camera (Hamamatsu Corporation, Bridgewater, NJ) and were printed using a Codonics NP-1600 dye-sublimation printer (Condonics, Middleburg Heights, OH).
Cell Counting
The number of positively stained cells in a random field of 1000 cells was counted. The average number of positive cells was obtained by counting 3 separate fields per section. Representative sections from each uterus were used in these studies; p values were calculated based on a one-tailed paired Student's t distribution.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To examine the effects of E2 and P4 on the expression of uterine ER, wild-type and PRKO mice were ovariectomized to eliminate endogenous hormones and then treated daily for 4 days with vehicle, E2 alone, or E2 and P4 (E+P). Uteri were then removed and 5-µm sections analyzed immunohistochemically using anti-ER antibodies (see Materials and Methods). The results of these analyses are shown in Figure 1 (wild-type mice) and Figure 2 (PRKO mice), and quantitation of positively stained cells is summarized in Table 1. Control uteri from wild-type mice administered vehicle alone revealed strong nuclear staining in a variety of cell types after incubation with anti-ER antibodies (Fig. 1, b–d), demonstrating constitutive expression of ER in epithelial, stromal, and myometrial compartments. The staining was specific for the anti-ER serum and was not observed with preimmune serum (Fig. 1a). Within the epithelial compartment, glandular epithelial (GE) cells (Fig. 1c) showed the strongest signal, with virtually all cell nuclei staining strongly positive. In contrast, scattered ER-positive cells were observed in the luminal epithelium (LE) and staining was less intense than in the GE (Fig. 1c). Strong staining for ER was observed in the stromal compartment with 76% of cell nuclei staining positive (Fig. 1c, Table 1). Myometrial smooth muscle (Fig. 1d) was also weakly ER positive. Comparative analysis of the expression pattern of ER in untreated PRKO mice (Fig. 2, b–d) demonstrated an expression pattern similar to that for wild-type mice, confirming that the apparent constitutive expression of ER is independent of PR activity.
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Treatment with E2 resulted in significant changes in ER expression patterns that were similar in wild-type (Fig. 1, f–h) and PRKO (Fig. 2, f–h) uteri. The intensity of ER staining in the GE was decreased; and while E2 had no significant effect on the intensity of ER staining in the LE (Fig. 1g), there was a significant increase in the number of LE cells expressing ER (Table 1, p < 0.01). Stromal ER staining was also decreased in terms of cell number and intensity (Table 1, Figs. 1g and 2g, p < 0.03). ER expression in the myometrial smooth muscle cells was increased in intensity by E2 treatment (see Figs. 1 and 2, b and d vs. f and h). Taken together, these data indicate that E2 can exert both positive and negative effects on expression of its own receptor depending on the uterine compartment in which the receptor is expressed.
Addition of P4 to the treatment regimen resulted in loss of E2-induced ER staining in the myometrium (Fig. 1l). This effect was clearly PR dependent since it was not observed in PRKO mice (Fig. 2l), indicating that PR acts as a negative regulator of ER expression in this compartment. Surprisingly, however, treatment with E+P resulted in a PR-dependent moderate increase in ER expression by the GE cells (see Fig. 1, j and k vs. Fig. 2, j and k). No such increase occurred in the LE (Fig. 1, j and k), which maintained the low level of ER expression seen with E2 treatment alone. Stromal staining was little changed from that seen with E2 alone (Fig. 1, j and k).
PR Localization and Regulation by E2 and P4
Immunohistochemical analysis of PR staining in uteri from ovariectomized wild-type mice in the absence of hormonal treatment revealed intense staining in the LE and GE with nearly all cells in these compartments staining positively for PR (Fig. 3, b and c). No staining was observed in uteri of PRKO mice under any treatment condition (Fig. 3, a, e, and i), indicating that the staining was specific for PR. In contrast to the epithelium, the myometrium and stroma showed only trace PR expression, with approximately 16% and 20% of the cells staining weakly positive for PR, respectively (Fig. 3, b–d and Table 1).
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E2 treatment (Fig. 3, f–h) resulted in opposing changes in PR expression in the epithelial and stromal compartments. Expression of PR in the epithelium was strongly down-regulated by E2 (Table 1, p < 0.001). However, while E2 treatment resulted in complete loss of PR expression in the LE (Fig. 3, f and g), PR staining in the GE was preserved, indicating a differential regulation of PR by E2 in these epithelial compartments (Fig. 3, f and g). In contrast to observations in the epithelium, E2 induced intense PR staining in the stromal compartment with about half of the cells staining positively (Fig. 3, f and g and Table 1, p < 0.01). The myometrium likewise showed a strong up-regulation of PR, with intense staining observed in 78% of myometrial cells (Fig. 3, f and h, and Table 1, p < 0.01). Thus, in addition to its ability to exert both positive and negative effects on expression of its own receptor, E2 exerts opposing compartment-specific regulatory effects on the expression of PR.
Addition of P4 to the treatment regimen resulted in a marked decrease in PR staining intensity in all compartments with an almost complete loss of detectable PR expression in the GE (Fig. 3, j–l), demonstrating a general negative feedback of PR activity on its own expression that is most prominent in the GE.
Regulation of Uterine Epithelial LF Expression by E2 and P4
To determine whether the differential regulation of PR in the GE and LE results in differential functional responses of these compartments to PR, we examined the expression of uterine LF, a glycoprotein expressed in and secreted by uterine epithelium under hormonal regulation [28, 31]. The protein has previously been demonstrated to be up-regulated by E2 in luminal and glandular epithelial cells and down-regulated by P4 [29]. In the absence of hormone, a low to moderate level of LF expression was observed in both wild-type and PRKO mice (Figs. 4, b–d and 5, b–d). Staining was predominantly cytoplasmic and, as expected, was confined to the LE and GE and to the glandular lumen. The observed luminal staining presumably corresponds to the presence of secreted LF.
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As expected, E2 treatment resulted in a large increase in both luminal and glandular epithelial LF staining in both wild-type and PRKO mice, with virtually all cells staining intensely (Figs. 4, f–h and 5, f–h). In E+P-treated wild-type animals (Fig. 4, j–l), however, LF staining showed a moderate decrease in the LE (Fig. 4, j and l) but was greatly decreased in the GE (Fig. 4k). This down-regulation of LF was not observed in PRKO mice (Fig. 5, j–e). Interestingly, while the majority of GE cells showed only low-level residual LF staining, scattered cells within each gland seem not to have responded to the P4-induced signal and continued to stain strongly for LF. This heterogeneous pattern of LF down-regulation within the GE, together with the lack of negative regulation of LF within the LE, is consistent with a direct regulation of LF by epithelial PR.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The effects of E2 are mediated in part by shifting ER expression away from the GE and stroma and into the LE and myometrium while also redirecting the expression of PR away from the LE and into the stroma and myometrium. In contrast, the effects of P4 are mediated in part by selectively inhibiting myometrial ER expression while maintaining GE ER expression and by generally decreasing the expression of PR.
The localization of ER to the epithelial, stromal, and myometrial compartments of untreated uteri observed in these studies is in agreement with previous immunohistochemical studies by others using sexually immature mice [18, 26, 32], demonstrating that basal ER expression does not change with sexual maturity. Further, the positive and negative regulatory effects of E2 on ER expression in the LE and stroma, respectively, are similar to those previously observed in immature mice [26]. This observation is interesting given the differential responsiveness of stromal cells to estrogen treatment in immature and mature mice [4].
The ability of E2 to alter the pattern of its own receptor expression indicates that different cell types within the uterus are capable of responding directly to E2 over the course of a 4-day E2 treatment. E2 is known to induce epithelial cell proliferation, hyperemia, and uterine inflammation [3–6]. The source or sources of ER that are responsible for the hyperemic and inflammatory effects are unknown at the present time. Recent studies using stromal and epithelial tissue recombination between wild-type and ERKO mice, however, have demonstrated that epithelial proliferation following E2 treatment is dependent upon stromal ERs and not epithelial ERs [20]. The ability of E2 to down-regulate ER in the stroma and at the same time redirect the expression of PR from the LE to the stroma indicates that the proliferative activity of stromal ERs may be self-limiting.
P4 strongly opposes the proliferative effects of estrogen in the uterine epithelium as well as its uterine inflammatory activity. In addition, P4 is known to induce proliferation of stromal cells [11] as well as to prime the uterus to respond to decidualizing stimuli [9, 10]. The inhibition of PR expression by E2 in the LE, and the E2-dependent up-regulation of PR in stromal cells observed in this study, are consistent with similar findings recently reported in adult rats using immunohistochemistry [27] and in mice using [125I]progesterone autoradiography [17]. Further, these findings support the hypothesis that stromal-derived PRs may be responsible both for the antiproliferative effects of PR in the epithelium and for the proliferative effects of PR in stromal cells.
The use of PRKO mice in these studies allows us to clearly delineate those effects of E+P treatment that are solely due to P4 and mediated by PR. Comparison of E+P-treated wild-type and PRKO mice has demonstrated that the effects of PR on ER expression differ in a compartment-specific manner. Our results indicate that the previously reported inhibitory role of P4 on uterine ER expression [25] is primarily due to a decrease in myometrial ER expression by P4. The observation that PR is expressed in the myometrium of E2-treated mice suggests that this inhibition of ER may be due to a direct effect of myometrial PR. In contrast, P4 appears to selectively inhibit E2-dependent down-regulation of ER in the GE in a PR-dependent manner while having no significant effect on expression of stromal or LE ERs. The absence of detectable PR staining in the GE suggests that this effect may be due to a P4-dependent paracrine signal from the stroma.
An interesting finding from this study is that the luminal and glandular epithelium display differential regulation of ER and PR expression. Thus, while E2 inhibits PR expression in the LE, expression of PR continues in the GE. This differential regulation of PR expression is reflected in a selective inhibition of LF expression in the GE but not in the LE, demonstrating that these compartments differ with respect to LF expression in their functional responses to P4.
Analysis of the expression of uterine LF provides important insights into how the interregulation of ER and PR can contribute to the functional responses of luminal and glandular epithelium to E2 and P4. With regard to basal LF expression, it has previously been reported that LF RNA could be detected in 7-day ovariectomized mice by Northern blot, but that no protein was detectable by immunohistochemistry until after E2 induction [33]. In this study, we demonstrate weak to moderate staining in the absence of hormone treatment. It is unclear whether this difference reflects a difference in the sensitivity of our detection or a difference in basal LF expression between the mouse strains used. The observation that E2 induces expression of epithelial LF is consistent with previous findings by Teng and colleagues [28, 31]. However, in contrast to previous observations demonstrating an inhibition of LF expression in both luminal and glandular epithelium after a single injection of E+P as well as in uteri of pregnant mice [29], our results show a differential inhibitory effect of PR on glandular rather than luminal LF. The differences observed in these analyses can be reconciled by hypothesizing that PR exerts a direct inhibitory effect on LF in the cells in which it is expressed. Since PR is initially expressed in glandular and luminal epithelium in the absence of hormone, a single injection of E+P would be expected to result in an inhibition of LF expression by epithelial PRs. However, continued hormonal treatment results in changing patterns of ER and PR expression, as discussed above, that result in an E2-dependent removal of PR from the LE and a down-regulation resulting in scattered PR expression in the glandular cells. Thus, prolonged E+P treatment would be expected to result in a selective inhibition of GE expression of LF in those cells in which PR is expressed as observed in the present study. In contrast to the sequential E2 followed by P4 effect observed in early pregnancy, the persistent inhibitory effect of estrogen on LE PR expression prevents a direct inhibition of LE LF by PR. Thus, the data are consistent with a direct inhibitory role of PR on epithelial LF expression.
In summary, our data support the conclusion that the proliferative and antiproliferative responses of the uterus to the E2 and P4 signals are mediated by interdependent changes in receptor expression through the epithelial and stromal compartments. In contrast to the view given by biochemical studies of whole uterus, we have shown that E2 and P4 have both positive and negative compartmentally specific effects on ER and PR expression in the mouse. The proliferative stimulus of E2 is partially self-regulating in that E2 lowers its receptor expression in the stroma, which is the source of the E2-induced proliferative signal to the epithelium. Further, the fact that E2 down-regulates PR in the epithelium and up-regulates PR in the stroma suggests that the E+P-dependent antiproliferative effect of PR on the LE may be imparted by a paracrine action of stromal PR. Finally, we have provided evidence that the functional responses to hormonal treatment of glandular and luminal cells within the epithelial compartment differ. This is reflected in a differential regulation of receptor expression as well as a differential regulation of a receptor-responsive epithelial target gene.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Orla M. Conneely, Dept. Cell Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. FAX: 713 798 7583; orlac{at}bcm.tmc.edu
Accepted: June 25, 1998.
Received: April 16, 1998.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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