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Regular Article |
and Prolactin on Intercellular Adhesion Molecule-1 Expression and Monocyte/Macrophage Accumulation in the Rat Corpus Luteum1
a Department of Animal and Nutritional Sciences, University of New Hampshire, Durham, New Hampshire 03824-3590
b Department of Animal Science, University of Wisconsin, Madison, Wisconsin 53706-1284
ABSTRACT
Expression of intercellular adhesion molecule-1 (ICAM-1) and the accumulation of monocytes/macrophages are inflammatory events that occur during PRL (PRL)-induced regression of the rat corpus luteum. Here we have compared the ability of prostaglandin F2
(PGF) and PRL to induce, in rat corpora lutea, inflammatory events thought to perpetuate luteal regression. Immature rats were ovulated with eCG-hCG and then hypophysectomized (Day 0), which resulted in a single cohort of persistent, functional corpora lutea. On Days 9–11, the rats received twice daily injections of saline, PGF (Lutalyse, 250 µg/injection), or PRL (312 µg/injection) to induce luteal regression. Surprisingly, luteal weight and plasma progestin concentrations (progesterone and 20-dihydroprogesterone) did not differ between PGF-treated rats and controls; whereas both luteal weight and plasma progestins declined significantly in PRL-treated rats. Furthermore, corpora lutea of PGF-treated rats and controls contained relatively minimal ICAM-1 staining and few monocytes/macrophages. In contrast, but as expected, corpora lutea of PRL-treated rats stained intensely for ICAM-1 and contained numerous monocytes/macrophages. In an additional experiment, there was no indication that luteal prostaglandin F2 receptor mRNA diminished as a result of hypophysectomy. These findings suggest that prolactin, not PGF, induces the inflammatory events that accompany regression of the rat corpus luteum.
corpus luteum, corpus luteum function, cytokines, ovary, progesterone, prolactin
INTRODUCTION
Prostaglandin F2 (PGF) induces regression of the corpus luteum in a number of species including the hamster [1], guinea pig [2], goat [3], pig [4], sheep [5], horse [6], and cow [7]. In these species, the spontaneous secretion of uterine-derived PGF initiates events that are thought to culminate in regression of the corpus luteum [8]. The characteristics of PGF-induced luteal regression include the precipitous decline of plasma progesterone (P4) concentration, as well as a variety of morphological effects, including the loss of luteal mass, the onset of apoptosis [9, 10], and more recently the induction of inflammatory processes [11–16].
In the rat, regression of the corpus luteum is also facilitated by inflammatory events, but occurs over several estrous cycles, and the role of PGF in this process is less certain. Acute in vivo effects of PGF include a decline of P4 synthesis [17, 18], decreased luteal membrane fluidity and increased phospholipase-A2 activity [19], diminished hCG binding to luteal tissue [19], and more recently, decreased expression of steroidogenic acute regulatory protein [20]. At least one study has shown that prostaglandin production within the rat corpus luteum may be necessary for rapid degeneration of tissue [21]. However, PGF has a very brief half-life in the rat and other species [22] and triggers only a transient decline of plasma P4 when administered to rats with high endogenous concentrations of prolactin (PRL) [18]. To our knowledge, the action of PGF to provoke inflammatory events in the rat corpus luteum, and to ensure the elimination of luteal tissue, has not been reported.
Only PRL that is recognized as an essential luteotrophic hormone in the rat [23] is also known, paradoxically, to induce luteal regression [23–27]. In hypophysectomized rats in which corpora lutea were hormonally induced, we have shown recently that a potentially important luteolytic effect of PRL is the induction of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) expression in the corpus luteum, and the accumulation of monocytes/macrophages [28–30]. Intercellular adhesion molecule-1 is thought to facilitate attachment of circulating monocytes to endothelial cells within the vasculature, and the subsequent transmigration of these cells as activated macrophages in response to chemokines [31]. Macrophages within the corpus luteum participate in cell-mediated killing by phagocytosis [32] and may ensure the elimination of luteal tissue by secreting cytotoxic factors and cytokines [11, 33–37].
The above observations compelled us to consider the role of PGF in the rat with respect to luteal regression, and in particular the ability of PGF to induce an inflammatory response within the corpus luteum as seen in other species. Here we compared the effects of PGF and PRL on inflammatory events in the rat corpus luteum. Specifically, expression of ICAM-1 and monocyte/macrophage accumulation were examined in conjunction with measurements of luteal weight and plasma progestin concentration following 72 h treatment of hypophysectomized rats with either PGF or PRL. In addition, mRNA for prostaglandin F2 (FP) receptor was measured in rat luteal tissue to determine if hypophysectomy influenced the expression of FP receptor.
MATERIALS AND METHODS
The University of New Hampshire Animal Care and Use Committee approved the experiments reported (IACUC no. 970403). Immature female Sprague-Dawley rats (30 days of age) were ovulated by s.c. injection of gonadotropins (5 IU eCG followed 56 h later by 5 IU hCG), and then hypophysectomized at 33 days of age. The injections and the surgeries were both performed by the vendor, Charles River Laboratories (Portage, MI). Methods similar to these result in the formation of a physiological number of corpora lutea (16–22 corpora lutea/rat) that persist for months [38] and produce 20-dihydroprogesterone (20-DHP) and small amounts of P4 for up to 40 days following hypophysectomy [27].
At 43 days of age, the rats were randomly assigned into three groups receiving twice-daily injections, i.m., of either 0.9% saline (control), PGF (Lutalyse; Upjohn, Pharmacia & Upjohn Company; Kalamazoo, MI; NDC no. 0009-0327-10, 250 µg per rat/injection), or PRL (ovine PRL; Sigma, St Louis, MO; L-6520, 312 µg per rat/injection in 250 µl of 0.15 M NaCl, 0.03 M NaHCO3, 0.1% BSA). All three groups (control, n = 11 rats; PGF, n = 8 rats; PRL, n = 11 rats) were treated daily for 3 days before decapitation at 46 days of age. Trunk blood was obtained from each rat for assay of plasma progestins (P4 and 20-DHP). The ovaries were removed and prepared for immunohistochemical staining of ICAM-1 and monocytes/macrophages and for measurement of luteal weight and content of FP receptor mRNA. The sella turcica of each rat was inspected for pituitary fragments using a dissecting scope; one rat was excluded from the experiment (PRL group) for an incomplete hypophysectomy.
An additional group of pseudopregnant, pituitary-intact rats was used to confirm the biological activity of the PGF preparation and to measure ovarian content of mRNA for FP receptor. The rats received injections of either saline (n = 9 rats) or PGF (n = 10 rats) essentially as described above except that the rats were not hypophysectomized at 33 days of age. Plasma P4 concentration was measured to detect the PGF-induced decline of P4 synthesis as reported previously [17]. The FP receptor mRNA was measured using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to detect potential differences in FP receptor mRNA expression between hyphophysectomized rats and pituitary-intact rats treated without or with PGF.
Immunohistochemistry (ICAM-1, Monocytes/Macrophages, and Activated Macrophages)
Ovaries were frozen in ornithine carbamyl transferase compound (OCT; Miles Laboratories, Inc., Elkhart, IN) and prepared as frozen sections (6 µm). Methods used to detect ICAM-1, monocytes/macrophages, and activated macrophages were similar to those described previously [28–30]. Tissue sections of ovaries from all treatment groups were stained simultaneously throughout all immunostaining procedures (10–12 ovarian sections per rat per antibody). Briefly, frozen tissue sections were air dried, fixed in 95% ethanol at 4°C for 10 min, and transferred to 0.3% H2O2 in methanol at 4°C for 15 min to quench endogenous peroxidase activity. Following quenching, the sections were rinsed three times (5 min each) in PBS containing 1% BSA (PBS-1% BSA) and then blocked with 10% normal horse serum for 15 min at 37°C. After the blocking step, the sections were again rinsed with PBS-1% BSA solution and then incubated with antibody for 1 h (ICAM-1) or 30 min (monocytes/macrophages) at 37°C. The following monoclonal antibodies were used as primary antibodies: mouse anti-rat ICAM-1 (IA29 clone, 1:1000; R&D Systems, Minneapolis, MN), mouse anti-rat monocyte/macrophage antibody (ED1 clone, 1:200; Chemicon, Temecula, CA), and mouse anti-rat activated macrophage antibody (ED2 clone, 1:200; Accurate Chemical and Scientific Corp., Westbury, NY). The specificity of each of these antibodies has been confirmed by previous studies [39–41]. For simplicity, monocytes/macrophages will be herein referred to as ED1-positive cells and activated macrophages as ED2-positive cells. Following incubation with primary antibody, the sections were then rinsed three times (5 min each) with PBS-0.1% BSA before incubation at 37°C for 30 min with biotinylated horse anti-mouse immunoglobulin (1:200 dilution). Amplification of the antigen-antibody complex was achieved using avidin-biotin-peroxidase (ABC kit; Vector/Novocastra, Burlingame, CA) for 30 min at 37°C. The color reaction was precipitated for all antibodies using 3-amino-9-ethylcarbazole (AEC kit; Vector/Novocastra) for 10 min at room temperature. Tissue sections were then rinsed, counterstained with hematoxylin, rinsed, and mounted using aqueous mounting medium (Dako Corporation, Carpinteria, CA). Nonspecific staining was assessed by omission of the primary antibody and was undetectable in all instances.
Immunohistochemical expression of ICAM-1 was assessed qualitatively by two independent observers. Slides were coded in random fashion prior to evaluation of all corpora lutea present in an ovary using a light microscope and 200x magnification. Observations of ICAM-1 staining were noted by the presence of a red precipitate. Staining ranged from little to no red coloration in the corpora lutea, to prominent peripheral and parenchymal staining. There was 95% agreement between the two observers in the general characterization of ICAM-1 staining. Numbers of monocytes/macrophages (ED1-positive cells) and activated macrophages (ED2-positive cells) were estimated using a light microscope and 400x magnification. The total number of positively stained cells per high-power field was counted. A red precipitate surrounding a darkly stained nucleus constituted a positively stained cell. Each field that was counted comprised a total area of 250 µm2. The average number of positively stained cells per high-power field was determined in two to eight nonoverlapping fields of two to seven corpora lutea for each rat. The mean of all fields counted for one rat represents n = 1.
Luteal Weight
Some of the rats had sufficient numbers of corpora lutea in both ovaries to permit processing of one ovary for immunohistochemistry (as described above) and the remaining ovary for dissection of individual corpora lutea (control, n = 9 rats; PGF, n = 8 rats; PRL, n = 8 rats). In these instances, the remaining ovary was rinsed in PBS (pH 7.0) and then dissected with magnification provided by a dissecting microscope. The corpora lutea were kept hydrated on Whatman (Clifton, NJ) no. 4 filter paper saturated with PBS during collection. For each rat, the average wet weight of corpora lutea was calculated by dividing the total weight of corpora lutea by the total number of corpora lutea (six or seven corpora lutea) per ovary. The average wet weight of the corpora lutea from one rat represents n = 1.
Measurement of FP Receptor mRNA
Due to the limited amount of tissue, mRNA was isolated and FP receptor mRNA quantified from pooled samples of ovarian tissue (pituitary-intact rats) and luteal tissue (hypophysectomized rats) using methods that were similar to those described previously [13, 42]. Briefly, magnetight oligo(dT) beads (Dynal, Lake Success, NY) were used to isolate mRNA and a semiquantitative RT-PCR assay was performed in triplicate on each pooled sample. Primers were specifically designed from rat sequences for FP receptor (Gene Bank U47287; nucleotides 684–704 and 977–996; 1 µM in PCR) and glyceraldehyde-3-phosphate dehydrogenase (G3PDH, Gene Bank X00972; 229–248 and 1000–1023; 0.1 µM in PCR). Samples were amplified for 30 PCR cycles (95°C for 30 sec, 58°C for 30 sec, 72°C for 30 sec) followed by 72°C for 5 min. The PCR products were separated on a 5% polyacrylamide gel, stained with ethidium bromide, and quantified with Collage software (Fotodyne, Hartland, WI). Intensity of the bands in each sample was compared, and results are expressed as the ratio of FP receptor mRNA to G3PDH mRNA in densitometric units.
Progestin Assays
Trunk blood was collected into heparin-treated tubes immediately after decapitation of hypophysectomized and pituitary-intact rats. Plasma concentrations of P4 and 20-DHP were measured by RIA in petroleum ether extracts of plasma according to methods described previously [43, 44].
Statistical Analyses
Numbers of ED1- and ED2-positive cells, plasma progestins, and luteal weight data were analyzed using ANOVA. Residual plots revealed heterogeneity of variance in the initial statistical analysis of the plasma progestin data. Therefore, these data were log transformed to minimize variance and reanalyzed. Tukey's multiple comparison procedure was used to further compare means among treatment groups. Differences in FP receptor mRNA expression were compared by t-test.
RESULTS
The administration of saline or PGF to hypophysectomized rats resulted in minimal ICAM-1 staining that was localized to the periphery of the corpora lutea and the most prominent blood vessels (arrows, Fig. 1, A–D). Conversely, corpora lutea of rats treated with PRL exhibited intense ICAM-1 staining along the periphery, and in some instances, ICAM-1 staining extended into the parenchyma of the tissue (arrowheads, Fig. 1, E and F).
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Corpora lutea of saline- and PGF-treated rats contained relatively few ED1-positive cells (Fig. 2, A–D; also Fig. 3), compared to the significant accumulation of these cells within corpora lutea of PRL-treated rats (Fig. 2, E and F; also Fig. 3). Similarly, the number of ED2-positive cells detected in corpora lutea of saline- and PGF-treated rats was minimal compared to the significant numbers found in corpora lutea of PRL-treated rats (Fig. 3).
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Luteal weights were similar in saline- and PGF-treated rats and were heavier than corpora lutea of PRL-treated rats (P < 0.01; Fig. 4).
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Plasma progestins (P4 and 20-DHP) did not differ between saline- and PGF-treated rats but declined significantly in rats treated with PRL after 72 h (Fig. 5).
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In pituitary-intact rats, plasma P4 decreased after 72 hr treatment with PGF (P < 0.05; 4.1 ± 1.0 vs. 1.9 ± 0.4 ng/ml for saline- and PGF-treated rats, respectively); but 20-DHP was not affected (P > 0.05). There was no difference in FP receptor mRNA concentration (P > 0.05) between hypophysectomized and pituitary-intact rats (Fig. 6). However, treatment of pituitary-intact rats with PGF decreased FP receptor mRNA concentration (P < 0.05; 0.51 ± 0.07 vs. 0.28 ± 0.03, unit ratio of FP receptor/G3PDH mRNA for saline- and PGF-treated rats, respectively; Fig. 6).
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DISCUSSION
The present study is the first to compare the separate effects of PGF and PRL to invoke ICAM-1 expression and monocyte/macrophage accumulation within the corpus luteum of hypophysectomized rats. Minimal staining for ICAM-1 and the sparse accumulation of ED1- and ED2-positive cells in corpora lutea of control and PGF-treated rats indicated an inability of PGF to induce these elements of the inflammatory response. In contrast, but as anticipated [30], PRL stimulated ICAM-1 expression and the accumulation of substantial numbers of ED1- and ED2-positive cells in the corpora lutea that was accompanied by a decline in luteal weight and progestin production. The most obvious ICAM-1 staining in control and treated rats appeared to be associated with the vasculature of the corpus luteum. Constitutive expression of ICAM-1 was evident within large blood vessels of the ovaries of control and PGF-treated rats, whereas expression induced by PRL extended to cells distributed throughout the steroidogenic parenchyma of each corpus luteum. The cellular source(s) of ICAM-1 within rat corpora lutea is uncertain and beyond the scope of this study but may include endothelial cells, monocytes/macrophages, fibroblasts, and possibly steroidogenic cells. Endothelial cells and monocytes/macrophages express ICAM-1 [45], and our observations are consistent with previous reports of constitutive and induced ICAM-1 expression in other tissues of the rat [46]. Further, these results confirm the ability of PRL to stimulate monocyte/macrophage accumulation within the rat corpus luteum and to facilitate luteal regression [29, 30, 47–49], but cast doubt on the capacity of PGF to induce similar regressive changes in the current rat model.
An inability of PGF alone to initiate an inflammatory response within the rat corpus luteum does not rule out the possibility that PGF promotes other aspects of regression, possibly in concert with PRL. A previous study found that indomethacin, an inhibitor of prostaglandin synthesis, blocked the PRL-induced decline of luteal weight in rats when placed in the ovarian bursa [21]. The authors concluded that the effects of PRL might be mediated by intraluteal prostaglandins, or that PRL is necessary for the effect of luteolytic prostaglandins. Prolactin is associated with increased phospholipase A2 activity and prostaglandin production within corpora lutea of postpartum rats [50]. Indeed, PRL-induced luteal regression may in part involve prostaglandins generated within the corpus luteum to augment regressive effects [51]. However, if intraluteal prostaglandins have a critical role in triggering inflammatory events, it is difficult to explain why in the current study consecutive injections of high concentrations of PGF (i.e., 500 µg per rat per day for 3 days) did not stimulate ICAM-1 expression or monocyte/macrophage recruitment. A possibility is that the amount of PGF reaching the ovaries following depot injections (i.e., i.m. injections), spaced at 12-h intervals, may be insufficient to have an effect. Constant infusion of PGF may be necessary to induce the inflammatory response. However, the injection protocol used in the current study is a modification of earlier work in the rat [19], in which effects of PGF were observed within a 24-h period.
There is ample evidence that PRL alone cannot initiate all aspects of luteal regression in the rat. Luteolysis is also influenced by the presence of P4, particularly for the induction of apoptosis [52, 53]. Gaytán et al. [52] found that in cycling rats, both PRL and P4 are necessary for the onset of apoptosis in the corpus luteum, but macrophage accumulation is dependent exclusively on the proestrous PRL surge. Similar findings have been reported by Guo et al. [53], who determined that apoptosis-associated gene expression in the rat corpus luteum is increased during periods of decreased P4, but prior to the proestrous PRL surge. Bowen and colleagues [47] have drawn similar conclusions, finding that blockade of the proestrous PRL surge alone does not prevent immune cell accumulation or apoptosis in the regressing corpus luteum. The results from the current study do not contradict these conclusions. However, while PRL alone may not initiate all facets of luteal regression in the rat, it appears to play a central role, more so than PGF, in triggering key elements of the inflammatory response and ultimately the elimination of luteal tissue.
In contrast to the action of PRL, administration of PGF to hypophysectomized rats for 24 h (unpublished observations) or up to 72 h (present study) did not alter the expression of ICAM-1 or the accumulation of monocytes and macrophages in luteal tissue compared to controls. The PGF used in this study was biologically active as demonstrated by the decline in plasma P4 and decreased FP receptor mRNA expression after PGF treatment of pituitary-intact rats (i.e., pseudopregnant rats). A cursory examination of ICAM-1 expression and of ED1- and ED2-positive cells in ovarian sections of these same rats, however, revealed no obvious changes in ICAM-1 or monocytes/macrophages compared to ovaries of pituitary-intact controls (unpublished observations). This suggests that although differences may exist between corpora lutea of hypophysectomized rats and corpora lutea of pseudopregnant rats, the inability of PGF to provoke ICAM-1 expression and monocyte/macrophage recruitment in the current study is not attributable to the animal model. Previous studies have shown that PGF decreases plasma P4 concentrations in rats due to induction of 20-hydroxysteroid dehydrogenase [54–56], but structural aspects of luteal regression, particularly conditions conducive to macrophage accumulation within the corpus luteum, may not follow this steroidogenic change without the influence of PRL [57]. Indeed, inhibition of steroidogenesis does not initiate luteal regression or augment PRL-induced luteal regression in the hypophysectomized rat [58]. Similar to the current study, inhibition of FP receptor mRNA by PGF has been reported in sheep, cow, and human cells [59–63], and PGF binding to rat luteal cells is reduced following PGF treatment [64]. In contrast, Olofsson and colleagues [65] report that PGF increases FP receptor mRNA concentrations in rats.
Prolactin is known to initiate a number of other aspects of luteal regression in the rat besides inflammatory processes. Increases in matrix metalloproteinase expression occur following PRL and are accompanied by decreases in DNA and protein content [57] and increases in apoptosis [47, 49, 52, 53]. Some of these effects may be associated with resolution of the inflammatory response. As phagocytic cells such as activated macrophages become engorged, they typically undergo apoptosis [66]. In addition, a number of cell types may be involved in PRL-mediated actions, each of which have receptors for and respond to PRL, including steroidogenic luteal cells [67], monocytes/macrophages [68], and T lymphocytes [49].
In contrast to the extensive luteolytic effects of PRL, PGF has been shown only to influence steroidogenesis in the rat, in particular, the sustained conversion of luteal P4 to 20-DHP [56]. Additional actions of PGF appear related to this steroidal effect, and include diminished luteal membrane fluidity and impaired hCG binding [19], and decreased steroidogenic acute regulatory protein expression [20]. However, none of these effects appear to be sustained for more than several hours, and none have been associated specifically with the loss of luteal tissue mass. Although it is known that several generations of corpora lutea coexist in the rat ovary [23], it is also clear that these older corpora lutea of previous estrous cycles become smaller and undergo regression in part due to inflammatory influences [28].
In summary, PRL but not PGF induces ICAM-1 expression and monocyte/macrophage accumulation in the corpora lutea of rats. We observed increases in the expression of ICAM-1 and the recruitment of monocytes and macrophages, coupled with decreases in luteal weight and steroidogenesis in only PRL-treated rats. These results call into question the role of PGF in regression of the rat corpus luteum, particularly with respect to the inflammatory response that occurs amidst the conversion of P4 to its inactive metabolite 20-DHP, and that ultimately results in the orchestrated elimination of luteal tissue.
ACKNOWLEDGMENTS
The authors thank Upjohn Pharmaceuticals for the gift of Lutalyse. We also thank Dr. P. Landis Keyes (The University of Michigan Medical School, Ann Arbor, MI) and S. Kitzsteiner of the P30 Center for the Study of Reproduction (P30 HD18258, Assay and Reagents Core Facility, The University of Michigan Medical School, Ann Arbor, MI) for conducting the plasma steroid assays.
FOOTNOTES
First decision: 25 August 2000.
1 Supported by U.S. Department of Agriculture grant 98–35208-6654 and by funds from the University of New Hampshire Vice President for Research. This manuscript is scientific contribution number 2059 from the New Hampshire Agricultural Experiment Station. 
2 Correspondence: D.H. Townson, Department of Animal and Nutritional Sciences, Kendall Hall, 128 Main St., University of New Hampshire, Durham, NH 03824-3590. FAX: 603 862 3758; dave.townson{at}unh.edu
Accepted: October 31, 2000.
Received: July 17, 2000.
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  M. C. Peluffo, R. L. Stouffer, and M. Tesone Activity and expression of different members of the caspase family in the rat corpus luteum during pregnancy and postpartum Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1215 - E1223. [Abstract] [Full Text] [PDF]
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