Molecular Human Reproduction, Vol. 5, No. 7, 642-650,
July 1999
© 1999 European Society of Human Reproduction and Embryology
Macrophage derived growth factors m odulate Fas ligand expression in cultured endometrial stromal cells: a role in endometriosis
1 Yale University School of Medicine, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, New Haven, CT 06520, USA
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Abstract |
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Fas–Fas ligand (FasL) interactions play a significant role in the immune privilege status of certain cell populations, and several cytokines and growth factors can modulate their expression. When a FasL-expressing cell binds a Fas-bearing immune cell, it triggers its death by apoptosis. In this study, we demonstrate that normal human endometrial epithelial but not stromal cells express FasL. Moreover, we showed that macrophage-conditioned media induced FasL expression by endometrial stromal cells in a dose-dependent manner. To elucidate which macrophage product was responsible for the up-regulation of FasL, endometrial stromal cell cultures were treated with the macrophage products platelet-derived growth factor (PDGF), transforming growth factor (TGF)-ß1, and basic fibroblast growth factor (bFGF). The first two (which are known to be elevated in the peritoneal fluid of women with endometriosis) induced a dose-dependent up-regulation of FasL expression, which was specifically inhibited by the antibody. Interestingly, bFGF (which is not elevated in peritoneal fluid of women with endometriosis) did not induce any response. These results suggest that the pro-inflammatory nature of the peritoneal fluid of women with endometriosis induces the FasL expression by regurgitated endometrial cells, and signals Fas-mediated cell death of activated immune cells. This could be a mechanism for endometrial cells to escape immune surveillance, implant and grow.
bFGF/Fas–FasL system/immunoprivilege/PDGF/TGF-ß1
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Introduction |
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Endometriosis, one of the most enigmatic gynaecological diseases, is characterized by the presence of endometrial cells, both epithelial and stromal, outside the uterus (Olive and Schwartz, 1993
). Retrograde menstruation has been accepted as a mechanism for transportation of endometrial fragments, their implantation into the pelvis, and their proliferation at the ectopic sites. However, while 76–90% of women experience retrograde menstruation (Bartosik et al., 1986), endometriosis affects only one in 15 women of reproductive age (Olive and Schwartz, 1993). This suggests that other factors, such as an impaired peritoneal environment, may determine a woman's susceptibility to developing endometriosis (Oral and Arici, 1996).
During the last decade, a growing interest has emerged in the role of the intraperitoneal environment in the pathogenesis of endometriosis (Ramey and Archer, 1993; Oral and Arici, 1996). Although macrophages are present in the peritoneal fluid under physiological conditions, an increased number of macrophages, as well as a higher activation level of these cells, have been reported in women with endometriosis (Haney et al., 1981; Halme et al., 1983, 1984, 1987). This is relevant since we know that activated macrophages express, synthesize, and release a great variety of growth factors, such as transforming growth factor (TGF)-ß, platelet-derived growth factor (PDGF) or basic fibroblast growth factor (bFGF) (Nathan, 1987). In addition, some of these macrophage products have been implicated in the pathogenesis of endometriosis (Nathan, 1987). Most recently, increased values of PDGF (Halme et al., 1988) and TGF-ß1 (Oosterlynck et al., 1994) have been found in the peritoneal fluid (PF) of women with endometriosis. Other growth factors, such as bFGF, did not show any increase in the PF of women with endometriosis (Seli et al., 1998).
The Fas–Fas ligand (Fas–FasL) system is a major pathway for the induction of apoptosis in cells and tissues (Nagata and Golstein, 1995). Fas, also called APO-1 or CD95, is a type I membrane protein of 45 kDa that belongs to the tumour necrosis factor (TNF)/nerve growth factor (NGF) receptor family (Nagata and Golstein, 1995). FasL, a type II membrane protein of 37 kDa, belongs to the TNF superfamily (Suda et al., 1993; Nagata and Golstein, 1995). Fas is expressed in various tissues such as thymus, liver, heart and kidney (Watanabe-Fukunaga et al., 1992), and its expression in thymus-derived (T) and bone marrow-derived (B) cells is enhanced after lymphocyte activation. In contrast, FasL expression is reported to be more restricted with predominant expression in activated T cells (Nagata, 1994; Suda et al., 1995). The Fas–FasL interaction has been implicated as a mechanism for clonal deletion, the control of T cell expansion during immune responses and in killing by cytotoxic T cells (Dao et al., 1996; Strand et al., 1996). More recently, FasL expression has been reported in non-immune cells, mainly in cells from immune-privileged tissues, suggesting that the Fas–FasL system may play an important role in the mechanism underlying this immune privileged status. Thus, FasL expression has been detected in stromal cells of the retina (Griffith et al., 1995), as well as in the Sertoli cells in the testis (Bellgrau et al., 1995). We, and others, have also described FasL expression in the human placenta and its role in trophoblast invasion/proliferation (Uckan et al., 1996; Runic et al., 1997; Mor et al., 1998), as well as in tumour cells (Gutierrez et al., 1998; Rabinowich et al., 1998) and in the brain (Bechmann et al., 1998).
Several reports have clearly shown how different cytokines and growth factors may regulate FasL expression (Ohtsuki et al., 1997; Ashley et al., 1998; Sata and Walsh, 1998). Even more, the capacity of human tissue macrophages to express FasL has recently been reported (Dockrell et al., 1998). In the present study, we tested the hypothesis that activated macrophage products induce FasL expression in endometrial stromal cells (ESC), thereby allowing them to escape immune surveillance, implant and grow within the peritoneal cavity.
Using reverse transcriptase–polymerase chain reaction (RT–PCR) and Western blotting, we demonstrated the up-regulation of FasL expression in ESC by PDGF and TGF-ß1, macrophage-derived growth factors which are found in increased levels in the peritoneal fluid of women with endometriosis. In contrast, bFGF, found at normal concentrations in the peritoneal fluid of women with endometriosis was found to have no effect on FasL expression by ESC. Thus, these data suggest that the Fas–FasL system may be involved in endometrial cell survival and implantation.
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Reagents
Roswell Park Memorial Institute (RPMI) 1640 and fetal bovine serum were purchased from Life Technologies (Grand Island, NY, USA). PDGF, TGF-ß1, bFGF and the anti-human PDGF polyclonal antibody were purchased from R&D Systems (Minneapolis, MN, USA). Other chemicals, unless otherwise specified, were obtained from Sigma Chemical Co (St Louis, MO, USA).
Tissue collection and cell culture
Endometrial cell preparation
Endometrial tissue samples were obtained from women undergoing diagnostic laparoscopy or hysterectomy for benign disease. Informed consent was obtained from each woman prior to surgery using protocols approved by the Human Investigation Committee of Yale University. Tissues were kept in Hank's balanced salt solution (HBSS) and transported to the laboratory for culture.
Endometrial cells were dispersed by incubation of tissue minced in HBSS containing HEPES (25 mM), penicillin (200 IU/ml), streptomycin (200 mg/ml), collagenase (2 mg/ml, 15 IU/mg), and DNase (0.2 mg/ml), 1500 IU/mg) for ~20 min at 37°C with constant agitation. The dispersed ESC were separated from glands by filtration through a wire sieve (73 µm diameter pore). Endometrial glands remained largely undispersed and were retained by the sieve, while stroma passed through into the filtrate. Immunohistochemical analyses of isolated cells were conducted using factor VIII as a marker of endothelial cells, cytokeratin as a marker of epithelial cells, vimentin as a marker of stromal cells, and 3C10 as a marker of macrophages. In primary cultures, endothelial cells, epithelial cells, and macrophages accounted for 10, 17, and 2% of the cells respectively, and the remaining were stromal cells.
Stromal cells were plated in Dulbecco's modified Eagle's medium (DMEM):Ham's F12 (1:1 v/v) containing antibiotics-antimycotics (1% v/v) and fetal bovine serum (FBS; 10% v/v) in plastic flasks (75 cm2), maintained at 37°C in a humidified chamber (5% CO2 in air) and allowed to replicate until confluent in monolayer. Thereafter, the cells were passaged by trypsinization and plated in 6-well dishes for RNA extraction and again allowed to replicate to confluence. At that stage, by immunohistochemistry, endothelial cells were not present, epithelial cells accounted for 0–7% of the cells, and macrophages accounted for 0.2% of the total. After cells reached confluence, cultures were treated with serum-free, Phenol Red-free media for 24 h before the treatment with growth factors was initiated. All treatments were conducted in serum-free, Phenol Red-free media as well. Individual cultures were set up for each patient. All the experiments were conducted on at least three different occasions.
Cell lines
The human choriocarcinoma Jar cell line and the myeloid leukaemia THP-1 cells were purchased from the American Type Culture Collection (ATCC; Rockville, MD, USA). Jar cells were plated in DMEM containing antibiotic–antimycotics (1% v/v) and FBS (10% v/v) in plastic flasks (75 cm2), maintained at 37°C in a humidified chamber (5% CO2 in air) and allowed to replicate until confluent in monolayer. After cells reached 70–80% confluence, cultures were treated with serum-free, Phenol Red-free media for 24 h before treatment with growth factors was initiated.
Induction of differentiation of THP-1 cells
The THP-1 myeloid leukaemia cells were induced to differentiate into macrophage-like cells by incubation for 48–72 h with phorbol methyl ester (PMA) at a concentration of 6 ng/ml.
Preparation of conditioned media
Differentiated macrophage-like THP-1 cells at a density of 1x106 cells/well were seeded in 6-well plates in Phenol Red-free RPMI 1640 medium with 10% FBS and supplemented with PMA (6 ng/ml). The cells were cultured at 37°C in a CO2 incubator for 24 h. The media was then removed from the plates, centrifuged and stored at 4°C for <48 h. These media were designated THP-1-conditioned media (CM). Non-conditioned media consisted of fresh Phenol Red-free RPMI 1640 medium with 10% FBS. Supplementation of the non-conditioned media was carried out as for the THP-1 CM (Mor et al., 1993, 1998b).
Incubation with macrophage-derived growth factors
ESC were treated with PDGF (10 ng/ml), TGF-ß1 (1 ng/ml), and bFGF (10 ng/ml) for 3, 6, 12, and 24 h prior to RNA and protein extraction. Dose–response experiments were performed with PDGF (0.1, 1, and 10 ng/ml) and TGF-ß1 (0.01, 0.1, and 1 ng/ml).
Blocking experiments
ESC were treated with PDGF (1 and 10 ng/ml), anti-human PDGF monoclonal antibody (1 µg/ml), and with PDGF at the aforementioned concentrations plus the antibody for 3 h before RNA extraction.
Preparation of total RNA and protein
Total RNA and protein were prepared from endometrial epithelial and stromal cells, and Jar cells using TRIzol® reagent (GIBCO BRL, Gaithersburg, MD, USA) according to the manufacturer's instructions. The TRIzol® method allowed us to extract RNA and protein from the same culture and, thus, from the same patient. This is an advantage since we were able to study the same samples at both the mRNA and protein level.
RT–PCR analysis
RT–PCR was performed using the RT–PCR kit from Pharmacia BioTech (Piscataway, NJ, USA) according to the manufacturer's directions. cDNA synthesis was performed with pd(N)6 0.2 µg and 1 µg total RNA. The primers used for amplification of FasL have been recently described (Strand et al., 1996) and have the following sequence: upstream, 5'-ATAGGATCCATGTTTCTGCTCTTCCACCTACAGAAGGA-3''; downstream, 5'-ATAGAATTCTGACCAAGAGAGAGCTCAGATACGTTGAC-3''. Each PCR cycle consisted of denaturation at 95°C, 1 min; annealing at 56°C, 1 min; and elongation at 72°C, 1 min, for a total of 30 cycles. The PCR products were analysed by gel electrophoresis.
The FasL signal was measured by densitometry and standardized against the actin signal using a digital imaging and analysis system (AlphaEase, Alpha Innotech Corporation; San Leandro, CA, USA). The linearity of the system was determined using serial dilutions of cDNA (Figure 1).
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Western blot analysis
Proteins were separated by sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS–PAGE) using 10% polyacrylamide gels and transferred to nitrocellulose membranes. Immunoblotting was performed after blocking the membranes with 5% powder milk. The primary antibody (FasL monoclonal antibody, clone 33, Transduction Laboratories, Lexington, KY, USA) was used at 1:1000 dilution. The secondary antibody (peroxidase-labelled horse anti-mouse, Vector, Burlingame, CA, USA), was developed with TMB Peroxidase substrate kit (Vector, Burlingame, CA, USA).
Co-culture DNA fragmentation assay (JAM test)
Target Jurkat cell (Fas-positive) death resulting from the co-culture with effector stromal cells (FasL-positive) was quantified by measurement of target cell DNA fragmentation using the JAM assay. (Matzinger, 1991) Adherent ESC were seeded into the wells of a flat 96-well microtitre plate at a cell number appropriate to give the required E/T ratios. Target Jurkat cell DNA was labelled by prior incubation with 10 Ci/ml of [3H]-TdR at 37°C for 24 h. Labelled Jurkat cells were washed and added to the seeded effector cells in a final volume of 200 µl/well. After co-culture at 37°C for 8–24 h, the cells were removed from the wells and filtrated onto glass fibre filters using an automatic 96 well filtration unit. The cells were then lysed with hypotonic buffer and their DNA was washed through the filter by four washes with D/D water. The radioactivity of intact chromosomal DNA retained on each filter was measured by liquid scintillation counting. Specific cell killing was calculated using the following equation (Matzinger, 1991):
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Expression of FasL in human endometrium
Determination of FasL mRNA expression by RT–PCR
To test the possibility that FasL was expressed in endometrial tissue, total RNA was extracted from cultured endometrial epithelial cell (EEC) and ESC cultures and evaluated by RT–PCR. In all cases studied, EEC cultures were found to express FasL mRNA at a level comparable to that of Jar cells. (Figure 2A
). However, we found variable FasL expression in different preparations of ESC cultures, 90% of the cases studied had undetectable FasL mRNA expression, while the remaining 10% showed low FasL mRNA levels. The reason for this difference is under investigation.
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Western blot analysis
To confirm FasL expression in endometrial cells, we performed Western blot analysis of whole cell lysates from the same patients and cultures from which we had previously obtained mRNA. As seen on Figure 2B
, the Western blot confirmed, at the protein level, the RT–PCR results. FasL protein was present in both EEC and ESC, but at a lower extent in the latter.
In-vitro regulation of FasL expression
Effect of macrophage-conditioned media on FasL mRNA expression
To evaluate the effect of activated macrophage secreted soluble products on FasL expression, ESC cultures were incubated with CM obtained from differentiated macrophages/THP-1 cells. FasL expression was analysed after a 24 h incubation using RT–PCR analysis. As shown in Figure 3, CM induced a marked increase in FasL expression detected at both the mRNA and protein level.
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PDGF, TGF-ß1, and bFGF modulation of FasL mRNA expression in ESC
To characterize the macrophage-secreted soluble growth factors which could mediate the observed effect of CM on FasL expression, ESC cultures were treated with PDGF, TGF-ß1, and bFGF and the expression of FasL was analysed both at the RNA and protein levels.
Time-course experiments:
Endometrial stromal cells were treated with PDGF (10 ng/ml), TGF-ß1 (1 ng/ml) and bFGF (10 ng/ml), and incubated for time intervals of 0, 3, 6, 12, and 24 h, after which the experiment was terminated. Treatment with PDGF or TGF-ß1 induced an early increase in the transcription of FasL observed at 3 h, and which gradually decreased at 6 and 12 h. Interestingly, no up-regulation of FasL expression was observed with bFGF, the only growth factor of the three tested which is not increased in the PF of women with endometriosis (Figure 4).
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Dose–response experiments:
A dose response was performed to assess the dependence of FasL transcription on increasing concentrations of PDGF and TGF- ß1. Endometrial cell cultures in 6-well plates were treated for 3 h with PDGF at concentrations ranging from 0 to 10 ng/ml, and with TGF- ß1 at concentrations ranging from 0 to 1 ng/ml. Both macrophage-derived growth factors induced a concentration dependent increase in FasL expression (Figure 5
).
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Blocking experiments:
To investigate the specificity of the up-regulation of FasL induced by PDGF, we performed blocking experiments. ESC cultures were treated for 3 h with PDGF at concentrations of 0, 1 and 10 ng/ml, and with a specific anti-human PDGF monoclonal antibody at a fixed dose of 10 µg/ml. A 65% reduction in the induction of FasL gene expression was observed when anti-PDGF was added together with 1 ng/ml of PDGF to ESC (Figure 6
). However, when the stimulus was stronger (10 ng/ml), the same concentration of anti-PDGF could only induce a 5% reduction (Figure 6).
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Effect of PDGF, and TGFß1 on FasL expression at the protein level
The FasL protein expression was examined by Western blot analysis of whole cell lysates. As demonstrated in Figure 7
, FasL was present in cell lysates obtained from ESC cultures treated for 24 h with either PDGF or TGF- ß1, confirming the previous mRNA findings.
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Fas-positive Jurkat cells are killed by PDG-treated stromal cells
In order to ascertain whether the FasL present on the stromal cells is functional we established a co-culture system in which ESC cells attached to 96-well plates were incubated with labelled Fas-positive Jurkat cells. As shown in Figure 8,
18% of Jurkat cells underwent apoptosis after 12 h of incubation with ESC previously treated with PDGF (10 ng/ml) while only 4% of Jurkat cells were induced apoptosis when co-cultured with untreated ESC (Figure 8).
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Discussion |
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If pregnancy is not achieved after ovulation, shedding of the endometrial tissue will occur in preparation for a new cycle. This physiological process is repeated ~400 times in the life span of a woman, and in up to 90% of the time, retrograde menstruation may occur, with shedding of menstrual debris into the peritoneal cavity (Bartosik et al., 1986
). Retrograde menstruation, the most widely accepted proposed mechanism of endometriosis, explains the presence of endometrial tissue in ectopic sites, but does not account for the fact that these misplaced cells survive in women with endometriosis and not in healthy control women. In the present study we test the hypothesis that macrophage products could confer to the endometrial tissue the status of immune privilege site, allowing it to implant in the peritoneal cavity and to escape immune surveillance. Moreover, we provide evidence that this mechanism is mediated by the Fas–FasL system.
Patients with endometriosis have characteristic immune system alterations (Steele et al., 1984; Gilmore et al., 1992; Oosterlynck et al., 1992), which probably are implicated in the pathophysiology of this condition. A paracrine/autocrine mechanism regulating the lymphocyte-mediated toxicity has been proposed (Hsu et al., 1997a) in which the concentration of potent inducers of natural killer (NK) activity is decreased in the peritoneal fluid of women with endometriosis. Other cytokines such as TNF-
, interleukin (IL)-1, IL-6 and IL-4 (Hsu et al., 1997b) show aberrant expression in the endometrial cells from women with endometriosis compared to healthy controls. These cytokines may have a role in the dysregulation of cell mediated and humoral immunological defense mechanisms involved in the peritoneal clearing. The release of endometrial soluble factors that inhibit immune cells may reduce the capacity of these cells to eliminate endometrial fragments.
Apoptosis, or programmed cell death, is an active signal-dependent process by which unwanted cells are deleted throughout life (Lincz, 1998). Apoptosis is involved in many physiological processes including tissue homeostasis, embryonic development, and the immune response. Its impaired activation is thought to contribute to the aetiology or pathogenesis of autoimmune disorders (Thompson, 1995). Mature peripheral T cells have shown their ability to trigger activation-induced cell death through the Fas–FasL system (Kabelitz et al., 1993).
The Fas–FasL system is a major pathway for the induction of apoptosis in cells and tissues. It has been shown to play an important role in the turnover of activated mature T cells and/or clonal deletion of autoreactive T cells in the periphery. Peripheral activated T cells express Fas. Upon binding to its ligand (FasL), Fas delivers an apoptotic signal that induces cell death (Nagata, 1994). More recently, FasL has been demonstrated to be expressed in non-immune cells, such as the testis, eye, trophoblast and cancer cells (Bellgrau et al., 1995; Griffith et al., 1995; Uckan et al., 1996; Runic et al., 1997; Mor et al., 1998). It has been suggested that expression of FasL by these cells protects the tissue from attack by T cells, which are killed through ligation of Fas. We believe that a similar mechanism may explain the survival of endometrial cells in the peritoneal cavity of women with endometriosis.
Endometriosis is associated with increased peritoneal fluid leukocyte activation, which causes a localized inflammatory response (Oral and Arici, 1997). Growth factors (GF) and inflammatory mediators produced by activated peritoneal leukocytes and macrophages may play a pivotal role in the establishment of endometriosis by facilitating the growth of endometrial cells at ectopic sites. For instance, activated macrophages secrete cytokines such as IL-8, capable of promoting endometrial cell growth and proliferation (Arici et al., 1998). We speculated that cytokines released at the microenvironment could up-regulate FasL expression in endometrial cells providing the means to defeat the immune system and escape immune surveillance. Activated T cells expressing Fas, in their attempt to delete the menstrual debris that reached the peritoneal cavity through retrograde menstruation, bind to the FasL expressed by endometrial cells, undergo apoptosis, thus allowing endometrial cells to implant and grow.
Our data strongly support this hypothesis. FasL expression is induced on endometrial cells by conditioned media obtained from in-vitro differentiated macrophages. Similar results are obtained with TGF-ß and PDGF, both macrophage-products (Shanker et al., 1995) known to be increased in women with endometriosis when compared to women without endometriosis. This effect is clearly specific since other macrophage-derived growth factors, such as bFGF, had no effect on FasL expression. Worth mentioning is the fact that bFGF is not increased in peritoneal fluid from women with endometriosis (Huang et al., 1996; Seli et al., 1998).
The effect of TGF-ß on ESC cultures is relevant in view of its presence in other immune privileged sites. It has been demonstrated that the microenvironment of certain immune privileged sites constitutively contains TGF-ß, which is able to inhibit the inflammatory response (Wilbanks and Streilein, 1992; Taylor et al., 1994). Therefore, we propose that one of the mechanisms by which TGF-ß and PDGF maintain the immune privileged status could be through the induction of FasL expression by the local cells which may alter the afferent antigenic signals, thus escaping the systemic immune system. Additionally, given the fact that TGF-ß and PDGF are chemotactic factors for inflammatory cells, and promote cell proliferation, differentiation and angiogenesis (Surrey and Halme, 1991; Chegini et al., 1992, 1994); they could also have synergistic effects on endometrial cells. Thus, TGF-ß and PDGF could help to promote endometriotic lesions, as well as induce FasL-mediated apoptosis in Fas-bearing activated immune cells (Figure 8).
A recent report described the invasive potential of E-cadherin-negative endometrial cells (Gaetje et al., 1997) suggesting that these cells might be the ones that migrate to ectopic locations, thus causing endometriosis. If the E-cadherin status of the endometrial cells is coupled with up-regulation of FasL, we may speculate that the immune escape stage would be set. Perhaps this may partially explain why EEC expressing FasL do not always implant at ectopic sites, if retrograde menstruation is seen in up to 90% of women.
In summary, ESC culture is a useful model in which to study the regulation of the Fas–FasL system. Moreover, our studies demonstrate the interaction between peritoneal macrophages and endometrial cells. Contrary to the expected cytolytic effect of these immune cells, the macrophage products may confer the endometrial cells with the means to escape immune surveillance. Thus, macrophage-derived growth factors which are elevated in women with endometriosis up-regulate FasL expression, which in turn, may induce apoptosis in activated T cells, permitting endometrial cells to survive in the peritoneal cavity. These findings provide new insights about the pathogenesis of endometriosis. At the same time, it opens the door for a new therapeutic approach, involving the use of immunomodulators.
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Acknowledgments |
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We thank the valuable technical contribution of Tracy Niven-Fairchild. J.G-V is a recipient of a grant from Fondo de Investigaciones Sanitarias FIS 98/5556, Ministerio de Sanidad, Madrid, Spain. This work was supported in part by DAMD17-98–1–8359 to G.M.
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Notes |
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2 Present address: IVI-Madrid, C/ Santiago de Compostela 88, 28035 Madrid, Spain
3 To whom correspondence should be addressed
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Submitted on November 9, 1998; accepted on March 29, 1999.
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