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Biology of Reproduction 60, 1299-1303 (1999)
©Copyright 1999 Society for the Study of Reproduction, Inc.

Articles

Expression of Macrophage Migration Inhibitory Factor Transcript and Protein by First-Trimester Human Trophoblasts1

Felice Arcuria, Marcella Cintorinoa, Rosella Vattia, Antonietta Carduccia, Sabrina Liberatorib, and Luana Paulesu2,c

a Institute of Pathological Anatomy and Histology, b Department of Molecular Biology, c Institute of General Physiology, University of Siena, Siena, Italy


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Macrophage migration inhibitory factor (MIF) was originally identified for its capacity to inhibit the random migration of macrophages in vitro. To date, the role of MIF as a pro-inflammatory cytokine, pituitary hormone, and counter-regulator of glucocorticoid action on the immune response is commonly recognized. Although recent studies suggest an involvement of MIF in reproduction, no data exist on the expression of this cytokine in early human pregnancy. In this study, we evaluated the presence of MIF protein and mRNA in specimens of chorionic villi from first-trimester human placenta. Tissues were obtained at 6–10 wk of gestation and analyzed by Western blotting, reverse transcription-polymerase chain reaction, and immunohistochemistry. Our results demonstrate that human villous tissue is a novel site of MIF synthesis. In addition, immunohistochemical analysis identified MIF protein in the cytotrophoblasts of both the inner layer of villi and in the trophoblastic cell islands. We speculate that in view of its proinflammatory features, MIF might play a critical role in human implantation and in early embryonic development.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Macrophage migration inhibitory factor (MIF) was the first cytokine to be discovered [1]. Nevertheless, most of our knowledge about this molecule has come from recent studies [2]. Besides its first known biological function—the inhibition of the random migration of macrophages in vitro—MIF plays an essential role in the process of inflammation, being involved in the enhancement of macrophage phagocytosis, increases in tumor necrosis factor {alpha} (TNF{alpha}), and interleukin (IL)-1ß secretion and counter-regulation of the anti-inflammatory effects of glucocorticoids [3–5].

MIF is a product of T lymphocytes and macrophages and is released in response to proinflammatory stimuli, such as microbial toxins, mitogens, specific antigens, or cytokines (TNF{alpha} and interferon-{gamma}, IFN-{gamma}) [6, 7], and also to physiological concentrations of glucocorticoids. An important source of MIF is the pituitary gland [8]. Interestingly, MIF is secreted by the same pituitary cells that release ACTH, which stimulates the secretion of glucocorticoids in the adrenal gland. Thus, it is believed that MIF secretion by the pituitary gland counter-regulates the inhibitory effects of glucocorticoids on the immune response at a systemic level [2].

High steady-state levels of MIF protein and mRNA have been detected in several human and murine organs and tissues, suggesting the ubiquity of this cytokine [9–12]. Recent findings have shown a possible involvement of MIF in reproduction. Suzuki et al. [13] demonstrated the expression of MIF mRNA in murine reproductive tissues (ovary, oviduct, uterus, and early embryo), and they detected MIF protein in murine serum and amniotic fluid [14]. Other authors reported the presence of MIF in the human ovary, both in the follicular fluid and in the granulosa cells [15]. The only report suggestive of the expression of MIF during human pregnancy is a study by Zeng et al. [16] that found a sarcolectin-binding protein in the placenta whose properties corresponded to those of MIF.

In the study reported here, we tested the hypothesis that MIF is expressed in human trophoblasts in the first trimester of pregnancy. In view of its involvement in the inflammatory and immune response, we hypothesized that MIF would play a critical role in implantation and in early embryonic development.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Materials

Anti-human MIF goat polyclonal antibody and recombinant human MIF were purchased from R&D Systems (Abingdon, UK). Horseradish peroxidase-conjugated rabbit anti-goat antibody was obtained from Calbiochem (San Diego, CA). All the chemicals were of analytical grade (Sigma Chemical Co., St. Louis, MO).

Methods

Tissue preparation First-trimester human placentas were obtained from 9 consenting patients undergoing elective termination of pregnancy by vacuum aspiration at 6–10 wk of gestation. Placentas were immediately rinsed in sterile Hanks' balanced salt solution (HBSS) at room temperature to remove excess blood, blotted dry, and carefully dissected with a razor blade. Chorionic villi were extensively washed in sterile HBSS and blotted, and aliquots for protein analysis and RNA extraction were snap-frozen and stored in liquid nitrogen. The remainder was fixed in 10% buffered neutral formalin and embedded in paraffin for histology and immunohistochemistry. Sections of each specimen were stained with hematoxylin-eosin and histologically examined by a pathologist. Only tissues from physiological pregnancy were included in this study.

Western Blot Analysis

Frozen villous tissues were thawed, minced with a razor blade, and homogenized on ice three times (20 sec each) with a Polytron (Kinematica, Lucerne, Switzerland), in 4 ml of 50 mM Tris-Cl, 5 mM magnesium acetate, 0.2 mM EDTA, 0.5 mM dithiothreitol, 1.0 mM PMSF, 10% (v:v) glycerol (pH 7.5), and 0.2% (v:v) of Triton X-100. After centrifugation at 750 x g for 10 min at 4°C, the supernatant was assayed for total protein content [17], and a volume of double-strength Laemmli buffer was added. Western blot analysis was carried out as previously described [18]. In brief, proteins were separated on a 14% polyacrylamide gel in the presence of SDS according to the procedure of Laemmli [19]. Twenty micrograms of total protein was loaded for each sample. After electrophoresis, the gel was removed and equilibrated in transfer buffer (20 mM Tris, 190 mM glycine, and 20% [v:v] 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% [w:v] dry milk in 10 mM sodium phosphate buffer, 0.15 M NaCl [pH 7.4], 0.1% [v:v] Triton X-100) for 1 h, 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 rabbit anti-goat antibody labeled with peroxidase (Calbiochem) at a dilution of 1:3000. The blot was washed three times with BS; once with 10 mM sodium phosphate buffer, 0.15 M NaCl (pH 7.4), 0.5% (v:v) Triton X-100; and twice with 0.05 M Tris-Cl buffer (pH 6.8). For detection, a chemiluminescence kit (Amersham International) was used according to the manufacturer's instructions.

Oligodeoxynucleotides

MIF primers were used for amplification by polymerase chain reaction (PCR). The 5' primer was 5 ' - C T C T C C G A G C T C A C C C A G C A G-3'; the 3' primer was 5 ' - C G C G T T C A T G T C G T A A T A G T T-3'. The expected size of the amplified fragment was 255 base pairs (bp) [12].

Detection of MIF mRNA

MIF mRNA was detected by reverse transcription (RT)-PCR. Total RNA was extracted using the method of Chomczynski and Sacchi [20]. Frozen villous tissues were crushed with a pestle and homogenized in Tri-Reagent (Molecular Research Center, Cincinnati, OH) with a Polytron, and RNA was extracted according to 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 (MMLV) reverse transcriptase (GeneAmp Kit; Perkin Elmer, Norwalk, CT) as previously described [21]. One microgram of total RNA was diluted in 10 mM Tris-HCl, 50 mM KCl, and 5 mM MgC12 (pH 8.3) containing 50 U of MMLV reverse transcriptase, 20 U of placental ribonuclease (RNase) inhibitor, deoxy-NTPs (dNTPs: 1 mM each of dGTP, dATP, dTTP, and dCTP), and 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.

PCR

Two microliters of RT reaction product was added to a mix containing 5-strength 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 cloned Thermus aquaticus DNA polymerase (Polymed, Florence, Italy), and MIF primers (final concentration 0.4 µM) in a volume of 50 µL; and the mixture overlaid with two drops of mineral oil (Sigma Chemical Co.). 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.

Assessment of PCR Product

PCR product identity was confirmed by restriction analysis. In brief, the product of three randomly chosen MIF PCRs was extracted with phenol:chloroform and precipitated with ethanol. The amplified fragment was digested with RSA I (Sigma Chemical Co.) under the manufacturer's suggested conditions. The products were separated by 3% agarose gel electrophoresis, visualized by ethidium bromide staining, and photographed.

Immunohistochemistry

Immunohistochemistry was performed by an indirect peroxidase-conjugated method. Sections (4 µm) of paraffin-embedded tissues were cut, and after drying were dewaxed, rehydrated, and washed in Tris-buffered saline (pH 7.6, TBS). Sections were incubated with normal rabbit serum (DAKO, Copenhagen, Denmark) diluted 1:5 in TBS to prevent nonspecific binding, and excess serum was removed by blotting. MIF antibody was diluted 1:400 in TBS and applied to the sections, and the incubation carried out overnight at 4°C. Slides were then washed three times with TBS for 5 min and incubated with rabbit anti-goat antibody labeled with peroxidase (Calbiochem) at a dilution of 1:2000 for 30 min. After being washed three times for 5 min in TBS, sections were incubated in diaminobenzidine tetrahydrochloride in TBS with 0.01% hydrogen peroxide for 15 min. The reaction was stopped by washing the sections in distilled water, and slides were mounted and observed under a light microscope.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Western Blot Analysis

The presence of MIF in villous tissue was first assessed by Western blot analysis. Total homogenates of villous tissues from nine placentas were fractionated by SDS-PAGE and blotted onto nitrocellulose, and the filter was exposed to the anti-MIF antibody. As shown in Figure 1, the antibody recognized a single band with an approximate molecular weight of 12 kDa, comigrating with recombinant human MIF, in all of the specimens tested.



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  		FIG. 1. Western blot profile of total homogenates of placental villous tissues. Lanes 1–9, specimens of villous tissue. rM, Recombinant human MIF. The positions of the molecular weight markers (x 10-3) are indicated. Absence of immunoreactivity was obtained when nonimmune goat serum immunoglobulins were used to probe an identical blot (not shown).

RT-PCR

To determine whether the presence of MIF protein is reflected in the steady-state levels of mRNA, total RNA extracted from villous tissues was examined by RT-PCR. As shown in Figure 2, 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 nine specimens examined. The comparable intensities of the bands in Figure 2 suggest similar transcriptional levels in all the tissues tested. The identity of the MIF PCR products was confirmed by restriction analysis with RSA I. As shown in Figure 3, in all the samples examined, the 255-bp PCR-amplified fragment contained an RSA I site yielding products of the expected size.



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  		FIG. 2. RT-PCR analysis of MIF mRNA levels in placental villous tissue. Total RNA of each specimen was reverse-transcribed and amplified in the presence of MIF primers. The sizes of the molecular weight markers are indicated. Lanes 1–9, specimens of villous tissue; B, blank.



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  		FIG. 3. Verification of MIF PCR product by restriction analysis. The products of three amplification reactions were digested with RSA I. The undigested fragment (lanes 1, 3, and 5) and RSA I digests (lanes 2, 4, and 6) were analyzed by 3% agarose gel electrophoresis. Predicted sizes of RSA I fragments are 203 and 52 bp. The sizes of the molecular weight markers (lane M) are indicated.

Immunohistochemistry

Localization of MIF protein in the villous tissue was evaluated by immunohistochemistry. As shown in Figure 4, strong immunoreactivity was observed in trophoblasts of the chorionic villi (Fig. 4A). Observation at a higher magnification revealed that the staining was limited to the cytotrophoblast layer (Fig. 4B). Some of the villous stromal elements were also stained. In addition, as demonstrated in Figure 4C, MIF immunoreactivity was consistently found in the trophoblastic cell islands. Staining was abolished when nonimmune serum immunoglobulins were used instead of the MIF antibody (Fig. 4D).



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  		FIG. 4. Immunolocalization of MIF in placental tissues. Immunohistochemistry was performed by an indirect peroxidase-conjugated method. Chorionic villi original magnification: A) x200; B) x400. Trophoblastic cell island: C) x200 original magnification. Abolition of staining by replacing the primary antibody with nonimmune serum immunoglobulins: D) x200 original magnification. Reproduced at 71%.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In all the systems of viviparous reproduction, and in particular in those involving a highly invasive placenta, such as the hemo-chorial placenta of humans and rodents, complex regulatory mechanisms are required to allow the implantation and the growth of the semi-allogenic fetus in the maternal tissues [22]. Although an inflammatory response seems to occur at the time of implantation, both an immunosuppressive profile and a shift from cell-mediated immunity to humoral immunity seem to occur throughout most of the pregnancy [23, 24]. Implantation and gestation are linked to the secretion of soluble factors, cytokines, with immunomodulatory actions that act in an autocrine and/or paracrine fashion [25]. Cytokines are secreted by the chorion and/or uterine epithelium. While inflammation-associated cytokines, such as IL-1 and IL-6, have been demonstrated mainly during implantation [26, 27], cytokines with anti-inflammatory activities, such as IL-4, IL-5, and IL-10, seem to be secreted during the further development of the pregnancy [28]. The present study demonstrates for the first time that MIF, a cytokine involved in the inflammatory process, is produced by human trophoblasts in the first trimester of pregnancy. Our results extend those of Suzuki and coworkers [13], who demonstrated the presence of MIF mRNA in the murine embryo and blastocyst by suggesting that the secretion of MIF by embryonic tissues is a common event, at least in species with a highly invasive placenta.

The expression of MIF by the human placenta, as demonstrated in the present study, allows inferences on the roles played by this cytokine during pregnancy. Previous studies demonstrated that MIF represents the major binding protein of sarcolectin in the human placenta at term [16]. Sarcolectin is an antagonist of IFN{alpha}/ß, a potent regulator of cell growth and differentiation [29]. In our study, we demonstrated MIF expression in cells of the villous and extravillous trophoblasts, which we previously reported to express IFN{alpha}/ß receptors [30]. We speculate that the potential binding of MIF with sarcolectin could facilitate the action of IFN{alpha}/ß in these cells. Thus, as suggested for other tissues, trophoblastic MIF could play a physiological role in the control of growth of the fetal tissues into the maternal uterus. In addition, as proposed by Suzuki et al., embryonic MIF, based on its glutathione-binding activity, could favorably influence the development of the embryo by enhancing glutathione availability [13].

Il-10 is an immunosuppressant and anti-inflammatory cytokine, which was recently shown to play a critical role in the maintenance of pregnancy [31]. IL-10 is an antagonist of MIF since it reduces its synthesis by T cells and counteracts several MIF proinflammatory features, such as inhibition of macrophage random migration, activation and synthesis of NO, and NO synthase expression [32]. Human placental trophoblasts produce IL-10 [33]. In addition, MIF expression in early gestation trophoblast cells has been demonstrated in the present study. Considered together, these observations support the concept that MIF, like other proinflammatory cytokines (IL-1, IL-6), might act to counterbalance the antiinflammatory action of IL-10 during implantation. Furthermore, the role of MIF as an immunosuppressive cytokine inhibiting natural killer (NK) cell activity has recently been shown by Apte and coworkers [34]. NK cells are the leukocytes most represented in the human decidua [35]. On these bases, we speculated that trophoblast MIF may be involved in the creation of a suitable environment for the acceptance of the embryo by the maternal uterus.

Macrophages are the main target of MIF [3, 36]. MIF acts on these cells both by concentrating them at the site of inflammation and by increasing their adherence and phagocytosis, thus contributing to cell-mediated immunity. Activated macrophages have been associated with early embryo loss [37]. Nevertheless, substantial numbers of macrophages are present at the maternal-fetal interface, both in the chorionic villous mesenchyme and in the decidualized endometrium. It has been suggested that in a normal pregnancy, placental macrophages undergo a partial activation, sufficient to trigger phagocytosis to destroy bacteria but not to damage placental cells [38]. In addition, a recent report suggested roles for macrophages of the fetal-maternal interface as regulators of maternal T-cell tolerance to the fetal allograft [39]. Hence, it can be hypothesized that trophoblast MIF, keeping activated macrophages in situ, plays an important role in the maintenance of pregnancy.


   ACKNOWLEDGMENTS
 
The authors thank Dr. K. Thornburg of the Oregon Health Sciences University for his thoughtful reading of the manuscript.


   FOOTNOTES
 
1 Supported in part by grants from the Italian Government (MURST: Projects 60% and ex 40%) and from the Ferrero Foundation. Back

2 Correspondence: Luana Paulesu, Institute of General Physiology, University of Siena, Via Laterina, 8, 53100 Siena, Italy. FAX: 39 577 263 861; paulesu{at}unisi.it Back

Accepted: January 5, 1999.

Received: August 3, 1998.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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V. M. Abrahams, I. Visintin, P. B. Aldo, S. Guller, R. Romero, and G. Mor
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S. Chaisavaneeyakorn, N. Lucchi, C. Abramowsky, C. Othoro, S. C. Chaiyaroj, Y. P. Shi, B. L. Nahlen, D. S. Peterson, J. M. Moore, and V. Udhayakumar
Immunohistological Characterization of Macrophage Migration Inhibitory Factor Expression in Plasmodium falciparum-Infected Placentas
Infect. Immun., June 1, 2005; 73(6): 3287 - 3293.
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A. Akoum, C. N. Metz, and M. Morin
Marked Increase in Macrophage Migration Inhibitory Factor Synthesis and Secretion in Human Endometrial Cells in Response to Human Chorionic Gonadotropin Hormone
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L. Paulesu, C. Cateni, R. Romagnoli, F. Ietta, and V. Dantzer
Variation in Macrophage-Migration-Inhibitory-Factor Immunoreactivity During Porcine Gestation
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B. Wang and A. K. Goff
Interferon-{tau} Stimulates Secretion of Macrophage Migration Inhibitory Factor from Bovine Endometrial Epithelial Cells
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H. Yamada, E. H. Kato, M. Morikawa, S. Shimada, H. Saito, M. Watari, H. Minakami, and J. Nishihira
Decreased serum levels of macrophage migration inhibition factor in miscarriages with normal chromosome karyotype
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P. M. Drake, M. D. Gunn, I. F. Charo, C.-L. Tsou, Y. Zhou, L. Huang, and S. J. Fisher
Human Placental Cytotrophoblasts Attract Monocytes and CD56bright Natural Killer Cells via the Actions of Monocyte Inflammatory Protein 1{alpha}
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F. Arcuri, C. Ricci, F. Ietta, M. Cintorino, S. A. Tripodi, I. Cetin, E. Garzia, F. Schatz, P. Klemi, R. Santopietro, et al.
Macrophage Migration Inhibitory Factor in the Human Endometrium: Expression and Localization During the Menstrual Cycle and Early Pregnancy
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