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Biology of Reproduction 66, 361-366 (2002)
© 2002 Society for the Study of Reproduction, Inc.

Regular Article

Expression of Monocyte Chemoattractant Protein-1 and Distribution of Immune Cell Populations in the Bovine Corpus Luteum Throughout the Estrous Cycle1

David H. Townson2,a, Cindy L. O'Connora, and James K. Prub

a Department of Animal and Nutritional Sciences, University of New Hampshire, Durham, New Hampshire 03824-3590 b Vincent Center for Reproductive Biology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study characterizes the expression of monocyte chemoattractant protein-1 (MCP-1) and the relative distribution of immune cell populations in the bovine corpus luteum throughout the estrous cycle. Immunodetectable MCP-1 was evident in corpora lutea of cows at Days 6, 12, and 18 postovulation (Day 0 = ovulation, n = 4 cows/stage). Day 6 corpora lutea contained minimal MCP-1 that was confined primarily to blood vessels. In contrast, relatively intense staining for MCP-1 was observed in corpora lutea from Days 12 and 18 postovulation. MCP-1 was again most evident in the cells of the vasculature, but it was also observed surrounding individual luteal cells, particularly by Day 18. An increase in immunohistochemical expression of MCP-1 on Days 12 and 18 postovulation corresponded with increases in MCP-1 mRNA and protein in corpora lutea as determined by Northern blot analysis and ELISA. Monocytes and macrophages were the most abundant immune cells detected in the bovine corpus luteum, followed by CD8+ and CD4+ T lymphocytes. In all instances, Day 6 corpora lutea contained fewer immune cells than corpora lutea from Days 12 and 18. In conclusion, increased expression of MCP-1 was accompanied by the accumulation of immune cells in the corpora lutea of cows during the latter half of the estrous cycle (Days 12–18 postovulation). These results support the hypothesis that MCP-1 promotes immune cell recruitment into the corpus luteum to facilitate luteal regression. These results also raise a provocative issue, however, concerning the recruitment of immune cells several days in advance of the onset of luteal regression.

corpus luteum, corpus luteum function, cytokines, immunology, ovary, progesterone


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In a number of species, immune cell populations within the corpus luteum fluctuate throughout the estrous or menstrual cycle and are thought to have a role in maintenance and regression of the corpus luteum. In the rat [1–5], guinea pig [6], rabbit [7], pig [8, 9], sheep [10], horse [11], and human [12], for instance, an accumulation of macrophages within the corpus luteum accompanies luteolysis and is thought to facilitate tissue degradation and remodeling. Macrophages secrete an array of cytolytic agents [13–16] and have the capacity to engulf both cells and cell remnants [17]. More recently, a mechanism for the recruitment of macrophages within the corpus luteum during luteolysis has been postulated: the expression and secretion of monocyte chemoattractant protein-1 (MCP-1) by cells of the corpus luteum [2–4, 18–22]. MCP-1 is a member of the C-C chemokine ß subfamily and is one of the most potent molecules known to provoke monocyte/macrophage recruitment [23, 24]. The synthesis and secretion of MCP-1 within the corpus luteum can be stimulated by exogenous administration of luteolytic hormones [3, 4, 19, 20]. However, spontaneous expression of MCP-1 within the corpus luteum and its distribution relative to monocyte/macrophage populations has been examined only to a limited extent [2, 25].

In the cow, like in other species, immune cells (especially macrophages) are thought to influence maintenance and regression of the corpus luteum. Immune cells accumulate within the bovine corpus luteum around the time of luteolysis [25–28]. This may result from previous secretion of MCP-1 by the corpus luteum. The expression of MCP-1 mRNA has been assessed in the bovine corpus luteum by reverse transcription-polymerase chain reaction and in situ hybridization near the time of luteolysis [21] and in response to a luteolytic dose of synthetic prostaglandin F2{alpha} [19]. Yet, to our knowledge, the expression of MCP-1 mRNA and protein, and the temporal appearance of these products relative to the distribution of immune cell populations throughout the bovine estrous cycle, has not been examined.

The objective of the present study was to characterize the temporal expression of MCP-1 mRNA and protein relative to the distribution of immune cell populations within the bovine corpus luteum during early (Day 6), middle (Day 12), and late (Day 18) stages of the estrous cycle.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Collection of Luteal Tissue

The University of New Hampshire Animal Care and Use Committee approved the following experiments (IACUC 970202). Timed injections of GnRH (Cystorelin; a gift from Rhone Merieux, Inc., New York, NY) and prostaglandin F2{alpha} (Lutalyse; a gift from Pharmacia & UpJohn Co., Kalamazoo, MI) were used to synchronize ovulation (Day 0) in nonpregnant, lactating Holstein cows as described by others [29]. Briefly, cows received an initial injection of GnRH (100 µg i.m.) at an arbitrary stage of the estrous cycle and 7 days later were injected with prostaglandin F2{alpha} (25 mg i.m.) to initiate regression of the corpus luteum. Ovulation was then synchronized by a second injection of GnRH (100 µg i.m.) given 48 h after the prostaglandin F2{alpha} injection. Day of ovulation (Day 0) was defined by the disappearance of a large, preovulatory follicle as determined by scanning at 12-h intervals using transrectal ultrasonography. Ovulation occurred within 24–36 h of the second GnRH injection. Synchronization of the cows and collections of corpora lutea took place over a period of 4 mo; 3 cows were synchronized at a time (for tissue collections on Days 6, 12, and 18 postovulation), and this procedure was repeated on 4 occasions (n = 4 cows/stage postovulation). The corpora lutea were collected from the cows by transvaginal luteectomy [30]. A center slice was cut from each corpus luteum and then subdivided into 6 equivalent wedges for immunohistochemical processing. Each wedge of tissue was 2-mm thick and included both the center and peripheral regions of the tissue. Remaining portions of the corpus luteum were snap-frozen in liquid nitrogen for Northern blot analysis of MCP-1 mRNA and for ELISA of MCP-1 protein. A blood sample was obtained from each cow before tissue collection to assay plasma progesterone concentration [31].

Immunohistochemistry

Tissue wedges were processed in ornithine carbamyl transferase compound (OCT; Miles Laboratories, Inc., Elkhart, IN) using liquid nitrogen and isopentane and then prepared as frozen tissue sections (thickness, 6–8 µm). Frozen tissue sections were air-dried and fixed for 10 min in either ice-cold (4°C) periodate-lysine-paraformaldehyde fixative [32] for immunostaining of MCP-1 or ice-cold (4°C) acetone for immunostaining of immune cells. Tissue sections were quenched of endogenous peroxidase activity (0.3% H2O2 in methanol at 4°C for 15 min), rinsed briefly in PBS, and then rinsed 3 times (5 min each time) in PBS containing 1% (w/v) BSA (PBS-1% BSA) before blocking with 10% normal horse serum (30 min at room temperature). The sections were again rinsed in PBS-1% BSA and incubated with primary antibody (Table 1) overnight at 4°C. For a given antibody, tissue sections from all three stages of the estrous cycle were stained simultaneously throughout all immunostaining procedures. Following incubation with primary antibody, the tissue sections were rinsed 3 times (5 min each time) in PBS-0.1% BSA and then incubated with a biotinylated horse anti-mouse immunoglobulin (1:200 [v/v]) for 30 min at 37°C. 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 for all antibodies was precipitated using 3-amino-9-ethylcarbazole (AEC; Vector/Novocastra) for 10 min at room temperature. The tissue sections were then counterstained with hematoxylin, and coverslips were mounted using an aqueous mounting medium (DAKO Corporation, Carpinteria, CA). Nonspecific staining was assessed by preabsorption of the MCP-1 antibody with excess recombinant hMCP-1 and by omission of the primary antibody, and was undetectable in all instances.


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  		TABLE 1. Monoclonal antibodies used for immunohistochemistry

Quantification of Immune Cells

Using coded slides, positively stained cells were counted in 3 or 4 random fields per section (areas of connective tissue excluded) using a light microscope with a 10x objective (low-power field). A red precipitate surrounding a darkly stained nucleus constituted a positively stained cell. A total of 6–9 tissue sections per antibody per cow were counted. Each random field encompassed an area of 1 mm2. Thus, a total area of approximately 26 mm2 was examined during quantification. The average number of positively stained cells per low-power field (cells/lpf) from the corpus luteum of 1 cow represents n = 1.

Northern Blot Analysis of MCP-1 mRNA

Relative expression of MCP-1 mRNA was analyzed using total RNA extracted from bovine corpora lutea and methods similar to those described previously for rat luteal tissue [2]. In brief, 10 µg of total RNA were denatured (5 min, 70°C), electrophoresed in 1.5% agarose-formaldehyde gel, and passively transferred to nylon membrane (0.2 µm) by capillary blotting. Following transfer, the membrane was baked (2 h, 80°C) and prehybridized (50% formamide, 5x SSC [single strength: 0.15 M sodium chloride and 0.015 M sodium citrate], 50 mM NaPO4, 5x Denhardt solution, 0.1% SDS, and 0.1 mg/ml of salmon sperm DNA). The blot was then hybridized (15 h, 42°C) by adding an 800-base pair bovine MCP-1 cDNA probe (provided by Dr. Hellumut Augustin, Institute of Molecular Oncology, Tumor Biology Center, Freiburg, Germany) randomly primed with 50 µCi {alpha}-[32P]dCTP to the prehybridization solution. Following hybridization, the membrane was washed and exposed to x-ray film for 4 days. The membrane was then stripped and reprobed with radiolabeled 18S rRNA probe for normalization. Autoradiographic signals were converted to pixel-density values using the UnScan-It Automated Digitizing System, Version 5.1 (Silk Scientific Corp., Orem, UT).

Quantification of MCP-1 Protein

For measurement of MCP-1 protein, a sandwich ELISA kit originally developed for measurement of human MCP-1 (R&D Systems, Minneapolis, MN) but validated for detection of bovine MCP-1 by others [33] was used. Protein extracts of bovine corpora lutea were prepared by homogenization of whole luteal tissue in ice-cold PBS using a Polytron (Brinkmann Instruments, Westbury, NY). The homogenates were then centrifuged at 1000 x g for 10 min at 4°C to pellet any membrane fragments. Supernatant fractions were collected and snap-frozen (-80°C) before assay of MCP-1. The samples were also assayed for protein (BCA assay; Pierce, Rockford, IL) to normalize the MCP-1 results to total protein content. All samples were assayed in triplicate on a single plate.

Statistical Analysis

The immune cell, Northern blot, and MCP-1 ELISA data were analyzed by one-way ANOVA. Further differences among means for the 3 stages of the estrous cycle were analyzed using the Tukey multiple-comparison procedure.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
MCP-1 and Immune Cell Populations in the Corpus Luteum of the Bovine Ovary: Immunohistochemical Localization

On Day 6 following confirmed ovulation, immunostaining for MCP-1 was relatively minimal in the corpus luteum and was confined primarily to large blood vessels (Fig. 1). Little to no MCP-1 was noted in adjacent, nonvascular areas of the tissue (Fig. 1). In contrast, immunodetectable MCP-1 had increased markedly in corpora lutea on Days 12 and 18 (Fig. 1). On Day 12, MCP-1 was again most evident in the vasculature, including both large and small blood vessels (Fig. 1). By Day 18, vascular staining of MCP-1 was even more pronounced and, in some instances, completely surrounded individual cells of the parenchyma (Fig. 1). Nonspecific staining for MCP-1 was minimal (Fig. 1).



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  		FIG. 1. Immunohistochemical staining of MCP-1 within the corpus luteum for Days 6, 12, and 18 postovulation (reddish-stained areas). Immunodetectable MCP-1 in the Day 6 corpus luteum is evident in the vasculature (arrows) but not in lymphatic vessels (arrowheads). In the Day 12 and Day 18 corpus luteum, immunodetectable MCP-1 is again evident in the vasculature and, in some instances, extends to spaces surrounding individual luteal cells (arrowheads). Higher magnification of a blood vessel within adjacent luteal tissue sections in which the primary antibody was added (+) or preabsorbed with excess recombinant hMCP-1 (-). Bar = 100 µm

Monocytes were the most abundant immune cell type detected in the corpora lutea (range, 28–106 cells/lpf) (Figs. 2 and 3). Numbers of monocytes were fewest in corpora lutea from Day 6 compared to corpora lutea from Days 12 and 18 (P < 0.05) (Fig. 3). Macrophages followed a similar pattern of distribution, corpora lutea from Day 6 contained the fewest macrophages compared to the relative abundance of macrophages in corpora lutea from Days 12 and 18 (P < 0.01) (Fig. 3).



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  		FIG. 2. Immunohistochemical staining of monocytes within the corpus luteum for Days 6, 12, and 18 postovulation (reddish-stained cells). Individual cells are denoted by arrows. Bar = 100 µm



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  		FIG. 3. Macrophages and monocytes were the most numerous immune cells detected in the corpus luteum. Numbers of macrophages and monocytes increased significantly on Days 12 and 18. Means within a cell type having no common letter differ significantly (P < 0.05, n = 4 cows/stage)

Helper T lymphocytes and cytotoxic/suppressor T lymphocytes (CD4+ and CD8+ cells, respectively) were detected in bovine corpora lutea at all 3 stages of the estrous cycle (Fig. 4, cytotoxic T lymphocytes shown). Helper T lymphocytes were the least abundant immune cell type detected in the corpora lutea (range, 3–33 cells/lpf) (Fig. 5). Fewer helper T lymphocytes were observed in corpora lutea from Day 6 compared to corpora lutea from Days 12 and 18 (P < 0.01)) (Fig. 5). Cytotoxic/suppressor T lymphocytes were more abundant than helper T lymphocytes, nevertheless, they followed a similar pattern of distribution. Corpora lutea from Day 6 contained the fewest cytotoxic/suppressor T lymphocytes compared to corpora lutea from Days 12 and 18 (P < 0.05) (Fig. 5).



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  		FIG. 4. Immunohistochemical staining of cytotoxic T lymphocytes (CD8+) within the corpus luteum for Days 6, 12, and 18 postovulation (reddish-stained cells). Individual cells are denoted by arrows. Bar = 100 µm



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  		FIG. 5. Cytotoxic T lymphocytes were more abundant than helper T lymphocytes but, nevertheless, followed a similar pattern of accumulation. More T lymphocytes were detected in corpora lutea on Days 12 and 18 than on Day 6. Means within a cell type having no common letter differ significantly (P < 0.05, n = 4 cows/stage)

Northern Blot Analysis of MCP-1 mRNA Expression in the Bovine Corpus Luteum: Comparison of Days 6, 12, and 18 Postovulation

Expression of MCP-1 mRNA was evident in corpora lutea of cows on all 3 days examined (Fig. 6). The relative amount of luteal MCP-1 mRNA (mean ± SEM) approximately tripled from Day 6 to Day 12 postovulation (0.28 ± 0.08 vs. 0.78 ± 0.11 densitometric units relative to 18S rRNA, respectively; P < 0.05) and remained elevated on Day 18 postovulation (P < 0.05 compared to Day 6) (Fig. 6). These results were consistent with the expression of MCP-1 protein as determined by immunohistochemistry and by ELISA (see below).



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  		FIG. 6. Expression of MCP-1 mRNA in bovine corpus luteum on Days 6, 12, and 18 postovulation. A representative Northern blot is depicted in the left panel. Increases in steady-state concentrations of MCP-1 mRNA relative to 18S rRNA were evident on Day 12 and Day 18 as determined by densitometry. Means having no common letter differ significantly (P < 0.05, n = 3 cows/stage)

Quantification of MCP-1 Protein in the Bovine Corpus Luteum: Comparison of Days 6, 12, and 18 Postovulation

Luteal content of MCP-1 increased in corpora lutea of cows on Days 12 and 18 postovulation compared to Day 6 (Fig. 7). However, variation of MCP-1 was highest on Day 12 compared to the other two days examined; thus, only Day 18 is statistically different from Day 6 (P < 0.05) (Fig. 7).



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  		FIG. 7. Increases in luteal content of MCP-1 observed in Day 12 and Day 18 bovine corpus luteum as determined by ELISA. Only Day 18 is statistically different from Day 6 (P < 0.05, n = 4 cows/stage)

Plasma Progesterone

Plasma progesterone concentrations confirmed that the corpora lutea obtained from cows on Days 6 and 12 were functional (range, 4.2–10.9 ng/ml, n = 8 cows). In contrast, the onset of regression of the corpus luteum was evident in 2 of 4 cows at Day 18 (mean, 2.6 vs. 9.2 ng/ml for the remaining 2 cows).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
A significant finding of the current study is that MCP-1 mRNA expression, MCP-1 protein secretion, and immune cell accumulation within the bovine corpus luteum preceded the onset of spontaneous luteal regression by several days. As early as Day 6 postovulation, MCP-1 expression was evident within the vasculature of the corpus luteum, but this was not accompanied by the accumulation of immune cells. Some degree of MCP-1 expression during early development of the corpus luteum might be necessary to aid tissue repair or to promote angiogenesis. In addition to its potent chemotactic activity, MCP-1 is recognized as an angiogenic factor [25, 34, 35]. In contrast to the Day 6 corpus luteum, the synthesis and secretion of MCP-1 by the Day 12 corpus luteum, and continuing through to the Day 18 corpus luteum, increased considerably and was accompanied by the significant accumulation of immune cells (i.e., monocytes, and to a lesser extent macrophages and CD4+ and CD8+ T lymphocytes). These results are consistent with previous observations in the rat, in which MCP-1 expression preceded, and was associated with, the appearance of monocytes/macrophages in corpora lutea at the time of luteal regression [2].

The above observations indicate that components of the immunological process of luteal regression (e.g., MCP-1, immune cells) are in place by Day 12 postovulation, possibly awaiting further activation by other factors. This scenario is consistent with the conceptual model of luteolysis in the cow proposed recently by Tsai and Wiltbank [36], in which the midcycle corpus luteum (Day 12) acquires the capacity to respond to prostaglandin F2{alpha} in a luteolytic fashion, whereas the early cycle corpus luteum (Day 4) does not. We suggest that part of this "acquisition of luteolytic capacity" extends beyond the increased expression of MCP-1 to include the marked accumulation of immune cells within the corpus luteum at this time. By inference, the importance of these immunological events might also extend to the period of maternal recognition of pregnancy. Pregnancy might suppress these immune response mechanisms, thus preventing regression of the corpus luteum. However, to our knowledge, no comparative studies have directly examined immune cell populations in the corpora lutea of nonpregnant and pregnant cows.

The occurrence of increased MCP-1 expression and immune cell accumulation within the midcycle corpus luteum also raises the question of whether the role of immune cells extends beyond simple elimination of luteal cells and cellular debris during luteolysis. Buford et al. [37] speculated that immune cells within the bovine corpus luteum contribute to a toxic effect that results in early embryonic loss in pregnant cattle. Cytokines, prostaglandins, and other secretory products of immune cells certainly might be responsible for such a toxic effect. Conversely, immune cells also modulate luteal steroidogenesis [38–42], suggesting that, under appropriate circumstances, immune cells enhance luteal function. In the current study, a significant accumulation of immune cells occurred within the corpora lutea of nonpregnant cattle several days before luteolysis. These results are consistent with our working hypothesis that immune cells promote regression of the corpus luteum. However, the mechanisms by which immune cells influence luteal function are poorly understood at the current time and offer further opportunity for investigation.

Immunohistochemical localization of MCP-1 occurred primarily in vascular areas of the bovine corpus luteum, in which smooth muscle cells and endothelial cells are found, although other cellular sources of MCP-1 cannot be excluded. More recently, we have found that endothelial cells derived from bovine corpora lutea secrete MCP-1 in vitro, and that secretion of MCP-1 by these endothelial cells is stimulated substantially by proinflammatory cytokines such as tumor necrosis factor-{alpha} and interferon-{gamma} (unpublished observations). These results support those of previous studies in which endothelial cells are described as a potent source of MCP-1 [43, 44], and they are consistent with those of a recent study by Senturk et al. [22], who reported vascular staining of MCP-1 within the human corpus luteum. However, other cell types might also contribute to MCP-1 secretion within the bovine corpus luteum. For instance, Penny et al. [21] found that CD8+ T lymphocytes increase in the bovine corpus luteum around the time of natural luteolysis, and that T lymphocytes are distributed in a pattern similar to cells in which MCP-1 mRNA was evident by in situ hybridization. In the current study, a similar increase of CD8+ T lymphocytes was observed within the bovine corpus luteum as regression became imminent. However, it should be noted that monocytes, macrophages, and CD4+ T lymphocytes also increased similarly to CD8+ T lymphocytes and, hence, may constitute additional sources of MCP-1 during luteal regression.

Our results differ from those of Goede et al. [25], who reported increases in MCP-1 expression and macrophage accumulation in bovine corpora lutea only undergoing regressive changes. The basis for this discrepancy is unclear, but it may be explained, in part, by the different methods used in the two studies to stage the corpora lutea. In the present study, corpora lutea were staged precisely to the time of ovulation in cows of known reproductive history and in which plasma progesterone concentrations were measured. This approach revealed that, although plasma progesterone had declined in 2 of 4 cows by Day 18 postovulation, luteal MCP-1 expression and immune cell accumulation was relatively equal among all 4 cows at this stage. In the report by Goede et al. [25], corpora lutea were obtained from cows at slaughter and staged according to morphological criteria. Hence, staging of the corpora lutea in their study did not permit precise determination of MCP-1 expression and immune cell recruitment relative to changes in plasma progesterone concentration and the onset of luteal regression.

In summary, the results of the present study indicate that an increase in MCP-1 expression occurs within the bovine corpus luteum during the latter half of the estrous cycle (Days 12–18 postovulation) and is associated with an accumulation of luteal monocytes, macrophages, and T lymphocytes. Expression of MCP-1 was detected primarily within the vasculature of the corpus luteum, and changes in MCP-1 expression were corroborated by analysis of MCP-1 mRNA and protein in homogenates of luteal tissue. The results support previous molecular evidence of MCP-1 within the bovine corpus luteum, and they extend these findings to suggest that increases in MCP-1 mRNA and protein coincide temporally with the accumulation of immune cells. Thus, MCP-1 is considered to have a role in the accumulation of immune cell populations within the bovine corpus luteum that occurs during luteal regression.


   ACKNOWLEDGMENTS
 
The authors wish to thank Dr. Joy L. Pate and Ms. Jodi Winkler (The Ohio State University, OARDC, Wooster, OH) for conducting the plasma progesterone assays.


   FOOTNOTES
 
First decision: 25 June 2001.

1 Supported by USDA grants 97-35208-4705 and 98-35208-6654. This manuscript is scientific contribution number 2089 from the New Hampshire Agricultural Experiment Station. Back

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 Back

Accepted: September 17, 2001.

Received: May 21, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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