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Regular Article |
a Institute of Pathological Anatomy and Histology and
b Institute of General Physiology, University of Siena, Siena 53100, Italy
c Department of Obstetrics and Gynecology, S. Paolo Institute of Biomedical Science, University of Milan, Milan 20129, Italy
d Department of Obstetrics and Gynecology, New York University Medical Center, New York, New York 10016
e Department of Pathology, University Central Hospital of Turku, Turku FIN-20521, Finland
ABSTRACT
Macrophage migration inhibitory factor (MIF) was discovered as an activated T-lymphocyte-derived protein that inhibits the random migration of macrophages in vitro. Subsequently, knowledge of the physiological actions of MIF was extended to include its role as a proinflammatory cytokine that affects several functions of macrophages and lymphocytes. Previous reports have suggested an involvement of MIF in reproduction. However, no data are currently available on the presence of this cytokine in the human endometrium. In this study, the expression and tissue localization of MIF was evaluated in specimens of cycling endometrium, first trimester placenta bed biopsy, and isolated endometrial glands by Western blot analysis, immunohistochemistry, ELISA, and reverse transcription-polymerase chain reaction. The results demonstrated that MIF is expressed in human endometrium across the menstrual cycle and in early pregnancy. Immunohistochemical localization identified the protein in glandular epithelium, in stromal and predecidualized stromal cells of cycling endometrium, as well as in the decidua of first-trimester placenta. The proinflammatory features and specific actions of MIF on lymphoid cells suggest its potential involvement in several aspects of endometrial physiology.
cytokines, reproductive immunology, uterus
INTRODUCTION
In mammalian reproduction, several features of key events such as ovulation, blastocyst implantation, menstruation, and parturition resemble those of the inflammatory and reparative processes in which cytokines and chemokines act as autocrine and paracrine mediators. Indeed, in recent years, many reports have widely documented the involvement of cytokines in the intercellular signaling that affects reproductive events, although their roles have not yet been completely defined [1].
The endometrium is a well-known site of cytokine synthesis and action. The presence of interleukins (ILs), tumor necrosis factors (TNFs), transforming growth factors (TGFs), colony-stimulating factors (CSFs), and interferons (IFNs) have been reported in cycling and pregnant endometrium. Although at times these results conflict concerning the site of synthesis and variations with the phase of the menstrual cycle or gestation, they strongly indicate that cytokines, acting either alone or in synergy, are involved in the cyclic changes of the uterine mucosa and in the regulation of uteroplacental functions [2].
Macrophage migration inhibitory factor (MIF) was discovered as a factor capable of inhibiting the random migration of macrophages in vitro. To date, its role as a proinflammatory cytokine involved in several aspects of immune response, as well as its expression in a variety of tissues, have been demonstrated extensively [3–6]. Recent findings have suggested a possible role of MIF in different aspects of reproduction, such as ovulation, blastocyst implantation, and embryogenesis. Thus, MIF mRNA and protein have been identified in murine and human ovaries as well as in human follicular fluid. In rodents, MIF has been detected in the amniotic fluid and in the early embryo [6]. In human pregnancy, a sarcolectin-binding protein whose properties corresponded to those of MIF has been described by Zeng et al. [7] in term placenta. A recent report from our laboratory has shown that MIF is expressed by first-trimester trophoblasts, where it can play a role during implantation and early embryonic development [8].
Despite these previous evidences, there are no indications available in the literature on the presence of MIF in human endometrium. In the study reported herein, the expression and localization of this cytokine was evaluated in endometrial specimens at different stages of the menstrual cycle and in early pregnancy. The results demonstrate that the human endometrium is a novel site of MIF synthesis.
MATERIALS AND METHODS
Anti-human MIF monoclonal and goat polyclonal antibodies, and recombinant human MIF were obtained from R & D Systems (Abingdon, UK). Horseradish peroxidase-conjugated rabbit anti-goat antibody was purchased from Calbiochem (San Diego, CA). All the chemicals were of analytical grade (Sigma Chemical Co., St. Louis, MO).
Tissue Samples
Samples of nonpregnant endometrium were obtained from consenting patients with normal menstrual cycles undergoing either hysterectomy for nonendometrial pathology or hysteroscopy for evaluation of the morphology of the uterine cavity. Subjects who had received steroid treatment during the previous 6 mo were not included in the study. All specimens were histologically examined by an experienced gynecological pathologist and only normal endometria were selected for further analysis. Endometrial tissues were classified according to the last menstrual period and by the histological criteria of Noyes et al. [9].
Uteri at different phases of the menstrual cycle (n = 39; age range 34–50 yr) were either fixed in 10% buffered neutral formalin and portions embedded in paraffin for immunohistochemistry (13 proliferative phase, 17 secretory phase), or used for endometrial gland isolation (5 proliferative phase, 4 secretory phase). Endometrial biopsies from hysteroscopy (n = 25; age range 26–39 yr; 8 proliferative phase, 9 early secretory phase, 8 late secretory phase) were rinsed in sterile Hanks balanced salt solution (HBSS) at room temperature to remove excess blood, and snap-frozen and stored in liquid nitrogen. Aliquots were fixed in 10% buffered neutral formalin and embedded in paraffin for histological analysis.
Early pregnancy endometrium (n = 4) was obtained from consenting patients undergoing elective termination of pregnancy at 6–10 wk of gestation, fixed in 10% buffered neutral formalin, and embedded in paraffin for immunohistochemistry.
Protein Analysis
Frozen endometrial tissues were thawed, minced with a razor blade, and homogenized on ice three times in 50 mM Tris-HCl, 5 mM magnesium acetate, 0.2 mM EDTA, 0.5 mM dithiothreitol, 1 mM PMSF, 10% (vol/vol) glycerol pH 7.5, and 0.2% (vol/vol) Triton X-100 with a Polytron (Kinematica, Lucerne, Switzerland). After centrifugation at 750 x g for 10 min at 4°C, the supernatant was assayed for total protein content and used for MIF detection by Western blot analysis and ELISA.
Western blot analysis was carried out as previously described [10]. In brief, proteins were separated on a 14% polyacrylamide gel in the presence of SDS according to the procedure of Laemmli [11]. For each sample, 40 µg of total protein of homogenate supernatant were loaded. After electrophoresis, the gel was removed and equilibrated in transfer buffer (20 mM Tris, 190 mM glycine, and 20% [vol/vol] methanol pH 8.3) for 30 min at room temperature. Proteins were transferred to nitrocellulose filters (Hybond-C, Amersham International, Little Chalfont, UK) for 3 h on ice. The blot was incubated in blocking solution (BS; 3% [wt/vol] dry milk in 10 mM PBS, 0.15 M NaCl pH 7.4, and 0.1% [vol/vol] Triton X-100) for 1 h and transferred to a 1:1000 solution of the anti-MIF antibody in BS, and incubated overnight at room temperature. The nitrocellulose filter was washed three times with BS and exposed at room temperature for 1 h to the rabbit anti-goat antibody labeled with peroxidase at a dilution of 1:3000. The blot was washed three times with BS, once with 10 mM PBS, 0.15 M NaCl pH 7.4, and 0.5% (vol/vol) Triton X-100; and twice with 0.05 M Tris-HCl buffer pH 6.8. For detection, a chemiluminescence kit (Amersham International) was used according to the manufacturer's instructions.
MIF was measured by a colorimetric sandwich ELISA. Ninety-six-well ELISA plates were coated with 100 µl/well of anti-human MIF monoclonal antibody (2.0 µg/ml) and incubated overnight at room temperature. The plates were washed three times with washing solution (10 mM PBS pH 7.4 and 0.05% [vol/vol] Tween 20), blocked by adding 300 µl of BS (10 mM PBS pH 7.4, 1% [wt/vol] BSA, and 5% [wt/vol] sucrose), and incubated at room temperature for 1.5 h. After washing three times, the tissue homogenate supernatant and the standard, appropriately diluted in Tris-buffered saline-BSA (20 mM Tris-HCl, 150 mM NaCl pH 7.3, 0.1% [wt/vol] BSA, and 0.05% [vol/vol] Tween 20), were added in duplicate (100 µl/well) and incubated for 2 h at room temperature. Plates were then washed three times and 100 µl of biotinylated goat anti-human MIF antibody (200 ng/ml) were added to each well and incubated for 2 h at room temperature. The plates were washed again and streptavidin horseradish-peroxidase (Zymed, San Francisco, CA) was added to each well and incubated for 20 min at room temperature. The plates were washed, and 3,3',5,5'-tetramethylbenzidine (Zymed) was added. After 20 min, the reaction was stopped by adding H2SO4. The absorbance was measured at 450 nm using an ELISA SR 400 microplate reader (Sclavo, Siena, Italy). MIF concentration was expressed as ng per mg of total protein content.
Immunohistochemistry
Immunohistochemistry was performed as described [12] using the streptavidin-biotin method. Sections (4 µm) were dewaxed, rehydrated, and washed in Tris-buffered saline (TBS; 20 mM Tris-HCl and 150 mM NaCl pH 7.6). Antigen retrieval was carried out by incubating sections in sodium citrate buffer (10 mM pH 6.0) in a microwave oven at 750 W for 5 min. Slides were preincubated with normal rabbit serum (DAKO, Copenhagen, Denmark) to prevent nonspecific binding, and incubated overnight at 4°C with the anti-human MIF goat polyclonal antibody diluted 1:300 in TBS. Slides were then washed three times with TBS for 5 min, and incubated with a rabbit anti-goat antibody labeled with biotin (Dako) at a dilution of 1:500 for 30 min. The reaction was revealed using the streptavidin-biotin complex (Dako). Sections were not counterstained. Slides were mounted and examined under a light microscope. For each case, a negative control was obtained by replacing the specific antibody with nonimmune serum immunoglobulins at the same concentration as the primary antibody.
Endometrial Gland Isolation
Endometrial glands were isolated from cycling endometria as described by Schatz and Gurpide [13]. In brief, tissues were trimmed, minced, and digested by type I collagenase (Worthington Biochemical Corp., Freehold, NJ). Glands and stromal cells were then separated by filtration through a 38-µm stainless steel sieve (Newark Wire Cloth Co., Newark, NJ). The glands were trapped on the sieve and the stromal cells passed through the sieve along with contaminating bone marrow-derived elements. The glands were backwashed from the sieve with HBSS and seeded on a tissue culture plastic Petri dish. The dish was placed for 30 min in a standard incubator at 37°C with a humidified atmosphere of 5% CO2/95% air. This procedure was repeated to purify the glands to virtual homogeneity. Thus, the glands remained floating while the other cell types preferentially attached to the plastic surface. The gland-enriched medium was then centrifuged for 10 min at 2000 x g at 4°C, the supernatant was discarded, and the pellet was stored at -80°C.
Oligodeoxynucleotides
MIF primers were used for amplification by polymerase chain reaction (PCR). The 5' primer was 5'-CTCTCCGAGCTCACCCAGCAG-3', the 3' primer was 5'-CGCGTTCATGTCGTAATAGTT-3'. The expected size of the amplified fragment was 255 base pairs [8].
Detection of MIF mRNA
MIF mRNA was detected by reverse transcriptase-PCR (RT-PCR). Total RNA was extracted using the method of Chomczynski and Sacchi [14]. Isolated endometrial glands were homogenized in Tri-Reagent (Molecular Research Center, Cincinnati, OH) with a Polytron and RNA was extracted following the procedure described by the manufacturer. RNA integrity was tested by agarose gel electrophoresis in the presence of 2.2 M formaldehyde.
First-strand cDNA was synthesized using Moloney murine leukemia virus (M-MLV) reverse transcriptase (GeneAmp Kit, Perkin Elmer, Norwalk, CT) as previously described [8]. One µg of total RNA was diluted in 10 mM Tris-HCl, 50 mM KCl, 5 mM MgC12 pH 8.3 containing 50 U of M-MLV reverse transcriptase, 20 U of placental RNase inhibitor, deoxy-NTPs (dNTPs; 1 mM each of dGTP, dATP, dTTP, and dCTP), 2.5 µM oligo(dT) primers in 20 µl of volume. The mixture was incubated at 42°C for 15 min, 99°C for 5 min, and 5°C for 5 min in a programmable thermal cycler (MJ Research, Watertown, MA). The blank for each RT reaction consisted of all of the reagents with water substituted for RNA.
Two µl of RT reaction product were added to a mix containing 5x reaction buffer (300 mM Tris-HCl, 75 mM [NH4]2SO4, 7.5 mM MgCl2 pH 8.5), dNTP mixture (final concentration 0.25 mM), 1.0 U of cloned Thermus aquaticus DNA polymerase (Life Technologies, Grand Island, NY), and MIF primers (final concentration 0.4 µM) in a volume of 50 µl, and the mixture was overlaid with two drops of mineral oil (Sigma). PCR was carried out in a programmable thermal cycler (Eppendorf, Netheler, Germany). Amplifications were carried out for 1 min at 94°C, 1 min at 60°C, and 1 min at 72°C for 30 cycles followed by a final 10 min at 72°C. For each reaction, a blank was prepared using 2 µl of the corresponding RT blank. One-fifth of each PCR solution was fractionated by electrophoresis in a 1.8% agarose gel. Gels were stained with ethidium bromide, destained, and photographed. PCR product identity was confirmed by restriction analysis with RSAI as previously described [8].
Data Analysis
The concentration values of MIF measured by ELISA in endometrial specimens at different phases of the menstrual cycle were compared by the Mann-Whitney U-test. Statistical significance was set at P < 0.05.
RESULTS
The presence of MIF in human endometrium was initially assessed by Western blot analysis in homogenates of specimens in both the proliferative (n = 7) and secretory phases (n = 6) of the menstrual cycle. Figure 1 shows that a specific anti-MIF antibody recognized, in all the specimens tested, a single band of the approximate molecular weight of 12 kDa, comigrating with recombinant human MIF.
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Tissue distribution of MIF protein in human endometrium was then analyzed by immunohistochemistry. Figure 2 shows images of sections of cycling and pregnant endometrium stained with the anti-MIF antibody. Immunoreactivity was present in both epithelial and stromal cells of all the specimens of cycling endometrium examined (n = 30; Fig. 2, A–C). Strong staining was observed in surface and glandular epithelial cells, although in the latter, the pattern of intracellular MIF distribution varied throughout the menstrual cycle. Thus, in proliferative-phase specimens (Fig. 2A), immunostaining was generally homogeneously distributed to the cytoplasm, whereas it was often more prominent in the apical portion of secretory-phase epithelial cells (Fig. 2B). Immunopositive material was also consistently found in glandular secretions (Fig. 2B). In endometrial stromal cells, a weak and homogeneous immunoreactivity was observed in both proliferative (Fig. 2A)- and secretory-phase endometrium (Fig. 2B). Moderate staining was present in predecidualized stromal cells (Fig. 2C) as well as in vascular endothelium (not shown). In early pregnancy endometrium, MIF positivity was evident in epithelial and in decidualized stromal cells of all of the specimens evaluated (n = 4; Fig. 2D).
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Quantitative evaluation of MIF tissue content in the cycling endometrium was carried out by ELISA. As indicated in Figure 3, no statistically significant differences were detected between specimens of proliferative (14.8 ± 3.5 ng/mg of protein [mean ± SEM]; n = 8), early secretory (15.9 ± 2.1; n = 9), and late secretory phases (18.9 ± 1.6; n = 8) of the menstrual cycle.
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To determine whether the presence of MIF protein in the epithelial cells is reflected in the steady state levels of mRNA, total RNA of glands isolated from specimens of proliferative phase (n = 5) and secretory phase (n = 4) endometrium was examined by RT-PCR. As shown in Figure 4, when amplification was carried out in the presence of human MIF primers, an intense band corresponding in size to the MIF product was obtained from the cDNA of each of the specimens examined. The identity of the PCR product was confirmed by restriction analysis with RSAI, which demonstrated in the 255-bp fragment the presence of an RSAI site yielding products of the expected size (not shown).
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DISCUSSION
Macrophage migration inhibitory factor was initially identified through its capacity to inhibit the random migration of macrophages in vitro. However, recent reports have demonstrated that this cytokine plays a more complex role in the immune response. MIF affects several key functions of macrophages such as phagocytosis, killing of intracellular parasites and tumor cells, and NO synthase expression [15–18]. Moreover, it acts as a proinflammatory cytokine, both by opposing the anti-inflammatory effects of glucocorticoids [19] and being released in response to proinflammatory stimuli such as microbial toxins and cytokines [20]. On the other hand, a recent report showed that MIF can also act as an immunosuppressive factor by inhibiting natural killer (NK) cell activity [21].
The present study is the first to demonstrate that MIF is expressed in human endometrium across the menstrual cycle and in early pregnancy. The results showed that MIF was predominantly expressed in the glandular epithelium. However, immunostaining was also found in the stromal and predecidualized stromal cells as well as in the first trimester decidua. No significant differences in endometrial MIF levels were detected across the menstrual cycle, although a slight relative increase was measured in secretory-phase tissues. These results differ from a previous report by Suzuki et al. [22] in the mouse uterus, which showed that MIF is localized in the tunica muscularis, and that its expression levels changed during the estrous cycle and in the preimplantation period. Thus, these findings indicate the existence of differences in uterine MIF localization and response to regulatory factors among species.
Despite the lack of an NH2-terminal signal sequence [5], MIF has been reported to be secreted by a number of cell types, including monocytes and macrophages, adipocytes, pituitary and epithelial cells [19, 23–25]. The results of the present report support the concept that human endometrial epithelial cells can also secrete MIF. Thus, as demonstrated by immunohistochemistry, in the secretory-phase glandular epithelium, the protein was mainly located on the luminal side, usually at the apical surface of the cells. Moreover, abundant immunoreactive material was present in the glandular secretion. These results are consistent with a previous study from our laboratory that demonstrated an apocrine pathway of MIF secretion in other human epithelial cells [25], and suggest that endometrial epithelial cells secrete MIF during the luteal phase of the menstrual cycle.
Macrophages are widely distributed in female reproductive tissues. In the endometrium, these cells represent an important mechanism of defense of its integrity and functionality. In the nonpregnant uterus, macrophage degradation of cellular debris and foreign material may be important in endometrial shedding and repair and in providing protection against infections. During pregnancy, macrophages are present at the fetomaternal interface, suggesting an involvement in both the response to infection, and in the immune interactions between fetal and maternal tissues [26]. Despite such important physiological functions, the mechanisms involved in recruiting, maintaining, and activating macrophages in the uterus are not fully defined. However, several studies emphasized the central role of cytokines in these processes. Thus, it has been shown that uterine cells are a potent source of cytokines with well-defined functions in promoting monocyte migration and activation, such as CSF-1, granulocyte-macrophage-CSF (GM-CSF), monocyte chemotactic protein-1 (MCP-1), and RANTES [26]. Macrophages are the main target of MIF, which acts on these cells by inhibiting migration and increasing their scavenger activity [3, 4, 15]. Based on this study, it is speculated that MIF may be involved in the mechanism determining macrophage accumulation and activation in the human endometrium.
The endometrium of pregnant and nonpregnant uterus is populated by NK cells. In the nonpregnant endometrium, the number of NK cells increases during the menstrual cycle and peaks in the late secretory phase. In early pregnancy, NK cells represent the most abundant leukocyte population in the uterine mucosa, with the largest number in the decidua basalis, the region of trophoblast invasion of maternal tissues. The physiological functions of uterine NK cells are unknown. It has been proposed, however, that in the nonpregnant uterus, they could affect growth, differentiation, breakdown, and regeneration of the uterine mucosa. In addition, in early pregnancy endometrium, these cells could influence implantation by controlling trophoblast invasion of the decidua and down-regulating the immune response to the semiallogenic fetus [27, 28]. Several studies have been directed toward comprehension of the mechanisms regulating the activity of NK cells in human endometrium. In this context, the observation that the cytolytic activity of uterine NK cells can be regulated by cytokines, acting either as stimulatory or suppressive factors, is relevant [29–31]. A remarkable feature of MIF is its immunosuppressive activity, as demonstrated by the recent study of Apte et al. [21]. These authors showed that MIF is able to inhibit NK cell-mediated cytolysis of both neoplastic and normal target cells, indicating that this cytokine can contribute to preserving immune privilege. Re-examination of these previous results in the light of the expression of MIF in the human endometrium as demonstrated in the present study, suggests the potential involvement of MIF in controlling uterine NK cell activity.
Emerging evidence suggest that important physiological functions of the human endometrium, such as menstrual bleeding and increased receptivity to the implanting blastocyst, are influenced by the local production of proinflammatory cytokines. In addition to its well-known action on macrophage migration, MIF also acts as a proinflammatory factor. MIF is induced by TNF
and IFN
and affects the macrophage release of TNF [20]. Furthermore, the enhanced release of MIF in response to physiological concentrations of glucocorticoids may override the steroid-dependent suppression of the synthesis of such cytokines as TNF, IL-1ß, IL-6, and IL-8 [19]. Finally, MIF can also act as an antagonist of anti-inflammatory cytokines, as demonstrated by a previous study on IL-10 [18]. It is therefore conceivable that MIF, acting directly or counterbalancing the action of anti-inflammatory factors, may play a role in the inflammatory response involved in the physiological changes of the human endometrium.
FOOTNOTES
First decision: 17 October 2000.
1 Supported by grants from the Government of Italy (MURST) and from the University of Siena. 
2 Correspondence: Luana Paulesu, Institute of General Physiology, Via Aldo Moro, Siena 53100, Italy. FAX: 39 0577 234 219; paulesu{at}unisi.it
Accepted: November 27, 2000.
Received: September 12, 2000.
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