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BOR - Papers in Press, published online ahead of print November 24, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.029058
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BIOLOGY OF REPRODUCTION 72, 949–953 (2005)
DOI: 10.1095/biolreprod.104.029058
© 2005 by the Society for the Study of Reproduction, Inc.

Variation in Macrophage-Migration-Inhibitory-Factor Immunoreactivity During Porcine Gestation1

Luana Paulesu3, Chiara Cateni3, Roberta Romagnoli3, Francesca Ietta3, and Vibeke Dantzer2,4

Department of Physiology,3 University of Siena, 53100 Siena, Italy Department of Basic Animal and Veterinary Sciences,4 The Royal Veterinary and Agricultural University, DK-1870 Frederiksberg C, Denmark


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The localization and activity of macrophage migration inhibitory factor (MIF) was investigated in the interhemal region of the noninvasive, diffuse, folded epitheliochorial placenta and in the nonpregnant uterus of the pig. MIF, a proinflammatory cytokine with many actions on macrophages and monocytes, may play an important role in materno-fetal immuno-tolerance during placental establishment, modulation, and growth. Immunohistochemical staining with anti-human MIF polyclonal antibodies was carried out on placental sections from 11 stages of gestation (16–95 days postcoitus) and on nonpregnant uterus at 13 days postestrus. Western blot analysis confirmed the specificity of the anti-human MIF polyclonal antibodies on pig tissues. MIF staining was intense in both the trophoblast and maternal epithelium in the early stages; in the later stages, it decreased dramatically in the maternal epithelium but remained high in the trophoblast. The uterine glands showed immunoreactivity at all stages, and the maternal and fetal epithelial linings of the areolar cavity showed high reactivity at Day 25. The vasculature also showed staining for MIF, and an intense to moderate staining was shown in the nonpregnant uterus, mostly in the surface and glandular epithelium. The high activity of MIF in the maternal and fetal tissues throughout placentation and its expression in the nonpregnant uterus indicate a regulatory role for MIF during embryo receptivity and epitheliochorial placentation.

cytokines, immunology, placenta, pregnancy, trophoblast


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Macrophage migration inhibitory factor (MIF) was first described as a protein secreted by T lymphocytes that inhibited the random migration of macrophages in vitro [1, 2]. More recently, it has been shown that MIF is produced by a number of other cell types, including macrophages, fibroblasts, and endothelial cells [3, 4]. MIF is a proinflammatory cytokine, a pituitary hormone, and a catalytic enzyme [5]. Furthermore, MIF has the unique ability to counteract the inhibition of cytokine production by glucocorticoids [6]. It also acts directly on the synthesis of proinflammatory cytokines such as tumor necrosis factor-{alpha} (TNF{alpha}), interferon-{gamma} (IFN{gamma}), and interleukin-1ß (IL-1ß), and plays an important role in cell growth and differentiation [7, 8]. MIF has been found in reproductive tissues of different animal species.

In mice, MIF mRNA is expressed in ovarian and uterine tissues in all stages of the estrous cycle, and in the preimplantation period [9]. MIF has been detected in murine maternal serum and amniotic fluid, whereas MIF mRNA and protein have been shown in oocytes and developing embryos [10, 11].

In humans, MIF mRNA is present in ovarian tissues and in the cycling endometrium [12, 13]. MIF has been also detected at different stages of pregnancy. In early gestation, we showed that MIF mRNA and protein are expressed by the proliferative and invasive trophoblast as well as by the maternal decidua [13, 14]. At midgestation, MIF is detectable in amniotic fluid [15]. At term pregnancy, a MIF-like protein is present in placenta, and immunoreactive MIF is expressed by fetal extraembryonic membranes [15, 16]. In cows, MIF has been reported in the corpus luteum and endometrium, and the epithelial endometrial cells also secrete MIF in response to IFN tau [17, 18].

Therefore, MIF seems to be intimately involved in reproduction. Because all the current studies of MIF in pregnancy have been carried out on animals with an invasive hemochorial placenta, we investigated a species with a true noninvasive, diffuse, folded epitheliochorial placenta, the pig. The findings could help explain the role of MIF in maternal-fetal homeostasis during implantation and establishment of pregnancy.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals and Tissue Collection

Porcine gestation is 114 ± 2 days. During early placentation, many changes occur until the materno-fetal interrelations and the typical architecture are established at Days 30–32 postcoitus (pc) [19–21]. The animals were either raised at an animal science research station in Gainesville, Florida, or they were conventionally raised Danish production animals. We sampled placental tissues after slaughter from 15 animals at 11 stages of porcine gestation: Days 16, 17 (n = 3), 19, 23, 25 (n = 2), 35, 48, 58, 70, 82, and 95 (n = 2), and from nonpregnant animals (n = 2) at 13 days postestrus. Three placentas were sampled from each animal. The three early stages were in situ-immersion-fixed via the uterine lumen, whereas the others were perfusion-fixed from the maternal side with 4% buffered formalin. Endometrium, alone or with adherent fetal membrane and placental tissues, was cut out and postfixed in the same fixative for 24 h, stored in phosphate-buffered saline (pH 7.4) solution, and subsequently embedded in paraffin and cut into 5-µm-thick sections. Placental tissues from animals at term of gestation were also collected for Western blot analysis. Tissues were rinsed in sterile Hanks balanced salt solution at room temperature to remove excess blood, then snap-frozen and stored in liquid nitrogen. Tissues of human placenta at term were either fixed in formalin and embedded in paraffin, or frozen in liquid nitrogen and used as positive controls for immunohistochemistry or Western blot analysis, as they were for pig tissues.

Immunohistochemistry

Immunohistochemical staining was performed at each of the reproductive stages described above using anti-human MIF goat polyclonal antibody (R&D Systems, Abingdon, U.K.). For each antibody on a day, sections from different stages of gestation were incubated together in the same batch.

After deparaffination in Bioclear (BioOptica, Milan, Italy) and rehydration in serial dilutions of ethanol, the histological sections were washed in Tris-buffered saline (TBS) pH 7.6 and preincubated with normal rabbit serum to prevent nonspecific binding. The slides were first incubated with anti-human MIF goat polyclonal antibody diluted 1:100, then with rabbit anti-goat antibody labeled with biotin (DAKO, Milan, Italy) diluted 1:500 in TBS, and finally with Streptavidin complex (DAKO) diluted 1:300. Each incubation was performed for 30 min at room temperature and was followed by three washes in TBS. The alkaline phosphatase reaction was revealed using naphthol and new fuchsin as a substrate. The endogenous alkaline phosphatase was blocked by the addition of 1 mM levamisole to the substrate solution. The sections were then washed for 5 min in running tap water and mounted with aqueous mountant Aquatex (Merck, Darmstadt, Germany). Negative controls were performed for each tissue by substituting the primary antibody with an isotype matched control antibody (R&D Systems) or TBS. Tissues from human placenta at term were used as positive controls. Evaluation and micrographs were carried out with a Leica DMR light microscope. The immunohistochemical staining was evaluated semiquantitatively by light microscopy, and the immunoreactivity was estimated on a scale of 0 to +++ (Table 1). A score of +++ indicates intense staining, whereas a score of 0 illustrates absent immunoreactivity. Scores of ++ and + indicate moderate and weak staining, respectively.


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  		TABLE 1. MIF immunoreactivity in porcine nonpregnant uterus and placenta during gestation.*

Western Blot Analysis

Specificity of anti-human MIF goat polyclonal antibody was tested by Western blot analysis carried out using pig and human placental tissues at term of gestation and recombinant human MIF (R&D Systems). Tissues were homogenized in ice-cold RIPA buffer (Tris-HCl 50 mM, NaCl 150 mM, Triton X-100 1% vol/vol, sodium deoxycholate 1% wt/vol, and SDS 0.1% wt/vol pH 7.5) supplemented with complete proteinase-inhibitor cocktail tablets (Roche Diagnostic, Mannheim, Germany). After centrifugation at 15 000 x g for 15 min at 4°C, the supernatant was assayed for total protein concentration using the Bradford assay and used for MIF detection by Western blot analysis.

Thirty micrograms of total proteins and 50 ng of recombinant MIF were resolved on 15% polyacrylamide gel in the presence of SDS according to the procedure described by Laemmli [22]. Proteins were then blotted to polyvinylidene difluoride membrane. Primary anti-human MIF polyclonal antibody was used at 1:1000. The membrane was then exposed to horseradish peroxidase-conjugated rabbit anti-goat antibody diluted 1: 10 000. The bands were finally detected by an enhanced chemiluminescence kit (Perkin-Elmer Life Sciences, Boston, MA) according to the manufacturer's instructions.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
MIF immunostaining was observed, albeit with a variable pattern, in all stages examined (results are summarized in Table 1). In the early gestational stages, MIF immunostaining was intense in both the trophoblast and the maternal epithelium. The immunostaining was intense throughout the cytoplasm of the trophoblast, whereas the reactivity in the opposed uterine or maternal epithelium was localized mainly in the basal compartment of the cells and in the apical compartment of many cells from Day 16 to Day 19 (Figs. 1–3). This cellular pattern showed some variability in the later stages. At Day 25, the staining generally remained intense in both the maternal epithelium and the trophoblast; however, the activity showed great variation among cells, from strong to weak (Figs. 4 and 5). Thereafter, the immunoreactivity decreased markedly to none or to very faintly weak in the maternal epithelium in the interareolar region, whereas the trophoblast continued to show intense to moderate immunoreactivity at Days 82–95 (Figs. 6 and 7). This activity tended to be intense in the columnar regions at the base of the fetal ridges and moderate at the top of the fetal ridges, where most gaseous exchange takes place (Figs. 6–7). Controls from this stage are shown in Figure 8. In the nonpregnant uterus, the uterine epithelium showed intense to moderate staining (Fig. 9). In the areolar gland subunit, both the trophoblast and maternal epithelium showed intense, uniform staining until Day 95 (Fig. 10). In the areolae at later stages the immunoreactivity of the maternal epithelium remained intense, whereas that of the trophoblast becomes moderate to weak or absent (Fig. 12). Uterine glands showed immunostaining in the nonpregnant uterus as well as at all stages of gestation (Fig. 11). A semiquantitative analysis showed that MIF immunoreactivity in the uterine glands was stronger in pregnant uterus than in nonpregnant uterus, and it was decreasing with the advancing gestation age (see Table 1).



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  		FIG. 1. FIGS. 1–9. MIF immunoreactivity in porcine placental tissues at Day 16 pc. Endometrial folds showing variable reactivity in the maternal epithelium (ME) and some slightly stronger activity in the trophoblast (Tr). The maternal connective tissue and cells in the fetal mesenchyme show weak to moderate immunoreactivity. FIG. 2. MIF immunoreactivity in placental tissues at Day 16 pc. Detail of the materno-fetal interface showing MIF immunoreactivity basally and apically in the maternal epithelium (ME). In the trophoblast (Tr), the reactivity is more evenly distributed within the cells. Immunoreactivity is also present in maternal connective tissue both in cells and in the intercellular matrix, as well as in endothelial cells of the maternal blood capillaries (MV). FIG. 3. MIF immunoreactivity in placental tissues at Day 17 pc. Endometrial folds showing variability of MIF immunoreactivity in the maternal epithelium (ME) and uniform reactivity in the trophoblast (Tr). The chorionic lining of the exocoelomic cavity, at the top, also shows positive staining. The maternal connective tissue shows some a weak immunoreactivity. FIGS. 4 and 5. MIF immunoreactivity in placental tissues at Day 25 pc. At the materno-fetal interface, the reactivity is intense in the maternal epithelium (ME) and trophoblast (Tr). However, some cells show less activity. In the maternal vessels (MV), capillaries (Fig. 4), a venule (Fig. 5), and the endothelial cells (arrowhead) show some staining. Connective tissue cells show some weak staining at both the maternal and fetal sides. FIG. 6. MIF immunoreactivity in placental tissues at Day 82 pc. The maternal epithelium (ME) shows no or weak staining, whereas the trophoblast (Tr) is intensely or moderately stained (see inset at higher magnification). The connective tissue cells show weak immunoreactivity. Staining was also observed in the capillaries (arrowheads). FIG. 7. MIF immunoreactivity in placental tissues at Day 95 pc. The immunostaining of the trophoblast (Tr) is intense and mainly localized in some cells, whereas the maternal epithelium (ME) shows weak or no reactivity. FIG. 8. Porcine placental tissues at Day 95 pc. Control section. The primary polyclonal antibody was substituted with Tris-buffered saline. No staining was observed. Trophoblast (Tr), maternal epithelium (ME), maternal vessel (MV). The red blood cells demonstrate the vessel lumen as dark dots due to underfocused condenser to make the tissues recognizable. FIG. 9. MIF immunoreactivity in nonpregnant uterine tissues at 13 days postestrus. Intense to moderate staining in the uterine lumenal epithelium (UE) and uterine glands (UtG). Vasculature (arrowhead)



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  		FIG. 10. FIGS. 10–12. MIF immunoreactivity in areola at Day 25 pc. The areola shows immunoreactivity in both, the maternal epithelium (ME) and trophoblast (Tr), whereas the secretion in the areolar cavity (A) is negative. FIG. 11. MIF immunoreactivity in areolar gland complex at Day 25 pc. Intense immunoreactivity is present in uterine glands (UtG) and vasculature (V). FIG. 12. MIF immunoreactivity in areola at Day 82 pc. Intense staining is present in the maternal epithelium (ME), whereas the trophoblast (Tr) is only weakly stained. Areolar cavity (A)

Some endothelial cells in capillaries and larger vessels showed immunostaining for MIF (Figs. 2–5, 6 insert, and 11). Connective tissue and cells showed moderate to weak immunoreactivity in early stages, declining to weak or nonimmunoreactivity in later stages of gestation. It was very weak in the nonpregnant uterus (see Table 1). All negative controls showed no reactivity, illustrated at Day 95 in Figure 8. Western blot (Fig. 13) analysis revealed a single band of 12 kDa in pig placenta as well as in human placenta comigrating with recombinant MIF.



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  		FIG. 13. Western blot profile. Specimen from pig (lane 1) and human (lane 2) term placenta. Recombinant MIF (lane 3). The position of the molecular weight markers (10–3) are indicated


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Cytokines are critical mediators of normal functions of the immune system and are involved in the regulation of growth, development, and activation of immune system cells. They are actively produced at the materno-fetal interface and are important actors in the cross-talk between the embryo and the endometrium [23].

Although the secretion of cytokines has been shown mainly in highly invasive hemochorial placentae, it has also been shown in less-invasive or noninvasive placentae. Thus, cytokines such as epidermal growth factor (EGF), insulin-like growth factor (IGF), IL-1 ß, vascular endothelial growth factor (VEGF), and IFN{gamma} are present in the porcine placenta [24–28], as well as in murine and human placentae [23, 29]. This study demonstrates that another cytokine—MIF—is also present in the porcine placenta.

We have shown that the intensity of MIF in the porcine placenta varies during gestation. In the early stages (Days 16–25), MIF immunoreactivity was intense in both the trophoblast and maternal epithelium, and moderate in the maternal parenchyma. There was a dramatic decrease in the maternal epithelium in the late stages (Days 82–95), whereas the immunostaining in the trophoblast remained relatively high. The vasculature also showed some staining for MIF. In the areolar gland complex, the uterine glands showed immunoreactivity at all stages. In the areolae, both the maternal and fetal sides showed very strong staining at Day 25. This changed at Day 82; the maternal epithelium still reacted rather strongly and the trophoblast reacted very weakly, whereas the opposite pattern was found in the interareolar regions. MIF immunostaining was also shown in nonpregnant uterus, mostly in epithelial and glandular cells.

The high immunoreactivity of MIF in both maternal and fetal tissues during the initial stages of placentation (until its establishment) and its expression in the nonpregnant uterus indicate a regulatory role for MIF during embryo receptivity and epitheliochorial placentation.

Evidence of MIF has been largely documented in murine and human tissues during gestation, as well as in ovary and nonpregnant uterus [9, 12–16]. MIF has been also detected in amniotic fluid and maternal serum throughout gestation [15]. Noteworthy, increasing or decreasing MIF concentrations have been shown in different reproductive events, including early gestation and term labor. An interesting paper by Yamada et al. [30] recently reported a decrease in serum MIF concentrations during early gestation in women with a normal karyotype but recurrent miscarriages. Moreover, in a recent report [15], we showed that MIF levels in amniotic fluid were higher at term than in midgestation, and higher in laboring than in nonlaboring women. Taken together, these data suggest that MIF, although ubiquitously present, is a major paracrine mediator in reproductive events. The present findings also indicate that MIF is a mediator in species with epitheliochorial-type as well as hemochorial-type placentation. In support of this, MIF is expressed by the bovine corpus luteum and endometrium [17, 18], and its secretion was shown in cultured endometrial epithelial cells. Although there are numerous studies on this, the role of MIF in endometrial function and placentation is not completely defined.

MIF is an important regulator of cell proliferation and angiogenesis in tumor tissues [31–33], but as shown here, MIF also interacts in placental angiogenesis in the pig. More recently, MIF has been identified as the endothelial cell growth-promoting agent released by ectopic human endometrial cells [34]. Moreover, MIF is expressed by active and early stage endometriotic lesions, suggesting that this cytokine is an autocrine/paracrine mediator of endometriotic growth and development [35]. The presence of angiogenic factors such as VEGF and its two specific receptors, Flt-1 and KDR, has been well documented in the porcine placenta [27, 36]. VEGF expression has been correlated with that of MIF in other tissues [37]. Thus, the presence of VEGF and MIF (present study) is evidence of potential paracrine vascular growth regulation during porcine placentation.

Macrophages are important components of the local cellular immune system in the sow endometrium [38, 39]. While there was no change in the number of macrophages in the surface epithelium in early pregnancy and in nonmated sows (at proestrus), there was a threefold increase in the subepithelial layer at Day 19 of gestation [39]. The mechanisms involved in recruiting, maintaining, and activating macrophages in the uterus are not fully understood, although cytokines appear to play a key role in these processes. In this regard, a report by Ramsoondar et al. [40] showed that growth factors that stimulate porcine macrophages are present in the supernatants of a porcine trophoblast cell line and Day 14 blastocysts. Macrophages are an important target of MIF; MIF inhibits migration of these cells and induces a variety of biological functions such as enhancement of adherence, phagocytosis, and induction of nitric oxide [41]. Macrophages are also an important source of MIF [3]. Thus, it can be suggested that MIF is involved in the mechanism that determines macrophage accumulation and activation at the materno-fetal interface via an autocrine/paracrine loop, being most active during early placentation in the pig.

Although these studies further support a role for MIF in pregnancy, MIF –/– mice did not exhibit reduced fertility [42]. However, the action of MIF has complex interactions with other cytokines [6]. Therefore, it can be hypothesized that other cytokines compensate for the deficiency of MIF. MIF is known to induce the synthesis of the proinflammatory cytokines TNF{alpha}, IFN{gamma}, and IL-1ß in cultured monocytes [43]. MIF in the human term placenta is a protein that binds to sarcolectin, the antagonist of type I IFN. This suggests that the presence of MIF in the human placenta can increase IFN activity [16]. In a positive loop, MIF secretion by endometrial epithelial cells is induced by type I IFN tau in ruminants [18]. Further studies are needed to clarify the role and interplay of MIF in different types of placentation.


   ACKNOWLEDGMENTS
 
We thank Dr. Peter Christie for his careful assistance in English.


   FOOTNOTES
 
1 Supported by a grant from the Danish Veterinary and Agricultural Research Council and by research grant PAR 2003 from University of Siena. Back

2 Correspondence: Vibeke Dantzer, Department of Basic Animal and Veterinary Sciences, The Royal Veterinary and Agricultural University, Gronnegaardsvej 7, DK-1870 Frederiksberg C, Denmark. FAX: 45 35 28 25 47; vd{at}kvl.dk Back

Received: 1 March 2004.

First decision: 16 March 2004.

Accepted: 2 November 2004.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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