Mol. Hum. Reprod. Advance Access originally published online on April 30, 2004
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Molecular Human Reproduction, Vol. 10, No. 7, pp. 489-493, 2004
Molecular Human Reproduction vol. 10 no. 7 © European Society of Human Reproduction and Embryology 2004; all rights reserved
Effect of mifepristone on the expression of cytokines in the human Fallopian tube
1Department of Woman and Child Health, Division for Obstetrics and Gynaecology, Karolinska Institutet, S-171 76 Stockholm, Sweden 2Department of Clinical Science, Division of Obstetrics and Gynaecology, Karolinska Institutet, S-141 86 Stockholm, Sweden
3 To whom correspondence should be addressed.; Email: kristina.gemzell{at}kbh.ki.se
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Abstract |
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Cytokines are believed to play a critical role as mediators between the oviduct and the developing embryo. A synchronous development of embryo and endometrium is essential to successful implantation. It seems to be beneficial for embryo development to rest for some time in the Fallopian tube. Expression of cytokines in the human Fallopian tube and the effect of mifepristone were investigated. Fourteen women with regular menstrual cycles and proven fertility, admitted to the hospital for tubal ligation, were randomly allocated to control or treatment groups. Mifepristone 200 mg was given on day LH+2. Surgery was performed on day LH+3 to LH+5. Biopsies were obtained from the ampullar and isthmic regions of the tubes. Expression of interleukin 8 (IL-8), tumour necrosis factor
(TNF), transforming growth factor ß (TGFß) and leukaemia inhibitory factor (LIF) was analysed using immunohistochemistry. All cytokines except IL-8 showed the same staining intensity both in the ampullar and isthmic region, while IL-8 was more pronounced in the ampullar region in both epithelial and stromal cells. Exposure to mifepristone made the spatial difference in IL-8 disappear and increased the expression of TNF in the epithelium of the isthmus, but had no effect on the expression of TGFß1 or LIF. Changes in cytokine expression in the Fallopian tube are likely to influence embryo development, which could contribute to the contraceptive effect of mifepristone. Key words: contraception/cytokines/Fallopian tube/mifepristone
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Introduction |
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The mammalian oviduct provides an optimal microenvironment for fertilization and early embryo development, and is therefore important for successful implantation (Senturk and Arici, 1998
). The morphological and functional characteristics of the oviduct are controlled by the ovarian steroids (Jansen, 1984). Estradiol increases the oviductal mass and stimulates differentiation of fully ciliated secretory epithelial cells. Progesterone suppresses the increase and differentiation and causes epithelial cells to be atrophied, deciliated and transformed to non-secretory cells (Donnez et al., 1985). Estrogen and progesterone also modulate the synthesis and secretion of human oviductal proteins (Arias et al., 1994). Estrogen and progesterone receptors (ER and PR) are present in the human Fallopian tube with an increased expression during mid-cycle. A spatially dependent expression of these receptors has also been found (Shah et al., 1999; Christow et al., 2002).
Progesterone plays a pivotal role in the reproductive processes. We have previously shown that administration of the progesterone antagonist mifepristone in the early luteal phase is an effective contraceptive method (Gemzell-Danielsson et al., 1993). The possible contraceptive mechanisms include the inhibition of embryo implantation due to the influence of endometrial development and function (Gemzell-Danielsson et al., 1994) and detriment of the peri-implantation milieu and preimplantation embryo development (Ghosh et al., 2000). Mifepristone is known to increase PR and ER of the oviduct in human and rhesus monkeys (Slayden and Brenner, 1994; Christow et al., 2002).
Cytokines are expressed in the endometrium in a cycle-dependent manner indicating a regulation by steroid hormones, and there are data indicating that cytokine expression in the Fallopian tube may also be cycle dependent (Palter et al., 2001). In vitro studies have shown that growth factors and cytokines are essential for cellular proliferation and differentiation of preimplantion embryos (Sharkey et al., 1995).
Several studies indicate that tumour necrosis factor- (TNF) has a negative impact on fertilization and early embryo development. TNFinfluences oocyte quality (Lee et al., 2000) and sperm motility (Estrada et al., 1997) and inhibits the proliferation of human placental trophoblast cells (Hunt et al., 1989).
Leukaemia inhibitory factor (LIF) increases blastocyst formation and hatching of human embryos in vitro (Dunglison et al., 1996). Ablation of endometrial expression of LIF or LIF receptor leads to implantation failure in the mouse (Stewart et al., 1992). Both LIF and LIF receptor are present in the human endometrium, which suggests that LIF is important also for the human implantation procedure (Aghajanova et al., 2003).
Transforming growth factor ß1 (TGFß1) inhibits proliferation of first trimester human cytotrophoblast cells in vitro (Graham et al., 1992). Mouse embryos homozygous or heterozygous for disrupted allele for TGFß1 gene suffer significant embryonic mortality characterized by defects in extra-embryonic tissues (Dickson et al., 1995).
Interleukin 8 (IL-8) combined with other factors can promote the development of mouse embryos (Ishiwata et al., 2000).
A possible mechanism of action of mifepristone when used for contraceptive purposes could be through an influence of oviductal function. Cytokines synthesized by the oviductal epithelium are believed to play a critical role as mediators between the oviduct and the developing embryo, which ensures the synchronous development essential to successful implantation. Disturbances in cytokine production during the peri-implantation period would be expected to adversely affect pregnancy outcome. In this study we examined the influence of 200 mg of mifepristone when given after ovulation on the expression of IL-8, TNF, TGFß1 and LIF in the human Fallopian tube during the early luteal phase.
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Materials and methods |
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Tissue collection
The study included 14 women (aged 26–45 years) with regular menstrual cycles (24–35 days interval) and proven fertility, admitted to the hospital for tubal ligation by laparoscopic technique. The Ethics Committee at Karolinska Hospital approved the study. All women gave written informed consent prior to inclusion into the study. None of the women had been treated with any hormonal contraceptives or used an intrauterine device for a minimum of 3 months prior to the study. The participants were randomly allocated to a control or a treatment group using sealed envelopes. Women allocated to the treatment group were given a single dose of 200 mg mifepristone immediately after ovulation day LH+2. Surgery was performed on day LH+3 to LH+5 in both the control and treatment groups. At surgery, biopsies were obtained from both sides of the Fallopian tube. The biopsy from the right side was taken from the proximal isthmic part of the tube while on the left side the biopsy was taken from the distal, ampullar part of the tube. Samples from the isthmic and ampullar part were prepared for morphological and immunohistochemical studies. The biopsies for immunohistochemistry were immediately frozen and stored in liquid nitrogen until analysed, while the biopsies for light microscope morphological evaluation were fixed immediately in Bouin's solution. (Bie and Berntser A-S, Abyhöj, Denmark.)
During the control and treatment cycles, daily morning urine samples were collected and analysed for estrone- and pregnanediol-glucuronide and LH using radioimmunoassays (Cekan et al., 1986). The homones were expressed in nmol per mmol creatinine for estrone- and pregnanediol-glucuronide and IU/mmol creatinine for LH (Metcalf and Hunt, 1976). For creatinine analysis, a commercial kit (Sigma Diagnostics, USA) was used. In addition, all subjects determined their own LH peak in urine samples collected twice daily from approximately cycle day 10 to LH+2 by using a rapid self-test (Clearplan; Searle Unipath Ltd, UK).
Morphological evaluation
The biopsies were embedded in paraffin, sectioned, dehydrated and stained with haematoxylin. Morphological evaluation of the samples was performed at the end of the study by one person who was unaware of the precise cycle day and whether the biopsy had been obtained in a control or treatment cycle.
Immunohistochemical analyses
The tubal biopsies were mounted in an embedding medium (OTC Compound; Miles Inc., USA) and serially sectioned to 9 µm using a Reichert–Jung Cryocut 1800 (Cambridge Instruments GmbH, Germany), and placed on poly-L-lysine-coated glass slides and immersed in 2% formaldehyde for 20 min for fixation. The slides were put into phosphate-buffered saline (PBS)/Saponin (0.1%), incubated 30 min in H2O2 (0.3% in MeOH) to block endogenous peroxidase activity, and then washed 2 x 3 min with PBS/Saponin. The sections were incubated with the primary antibody overnight in a humidified chamber at 4°C. The antibodies used are listed in Table I.
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The slides were washed in PBS/Saponin three times for 3 min each and incubated with 1.5% normal serum (in PBS/Saponin) from the animal which the secondary antibody was made from. Thereafter slides were incubated with secondary antibody diluted as 1:300 (goat anti-rabbit for TGFß1, horse anti-goat for LIF, IL-8 and TNF
horse anti-mouse for CD68) for 30 min at room temperature. The slides were then washed with PBS/Saponin three times for 3 min each prior to incubation with ABC complex (Vectastain Elite ABC immunoperoxidase detection system; Vector Laboratories Inc., USA, prepared according to the manufacturer's instruction). After washing with PBS/Saponin for three times, the slides were flooded with freshly prepared diaminobenzidine–hydrogen peroxide solution (DAB kit from Vector) and rinsed with distilled water. Slides were conterstained with 10% Mayer's haematoxylin (VWR, Sweden), washed for 10 min in cold water and mounted with glycerolgelatin. To check for primary antibody specificity, the primary antibodies were neutralized by adding the corresponding protein to the primary antibody, and incubated for 24 h at 4°C prior to analysis. Human placenta, endometrium or skin were used as positive controls as appropriate. Immunohistochemical staining was evaluated blindly by two independent workers, using a Zeiss light microscope at x200 magnification. The staining was graded on a scale of 0=0% stained cells, 1=faint (+, 1–30% stained cells), 2=moderate (++, 31–60% stained cells) and 3=strong (+++, 61–100%).
The differences in cytokine expression between different segments of the tube and the two groups were tested using Wilcoxon's signed ranks test or the Mann–Whitney U-test as appropriate. P<0.5 was considered to be statistically significant.
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Results |
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All control and treatment cycles were ovulatory with an LH peak. Urinary concentrations of estrone- and pregnanediol-glucuronide and LH were not significantly affected by the administration of mifepristone (data not shown). Biopsy material from one control was insufficient.
The morphological analysis revealed an expected difference between biopsies obtained at the isthmic or ampullar location but no obvious effect following treatment (data not shown).
TNF, TGFß1, LIF and IL-8 expression was detected in control and treatment samples from the isthmic and ampullar regions of the Fallopian tube (Figure 1). Immunostaining was present in the epithelial stromal and endothelial cells. In the epithelial cells, the staining of these four cytokines was mainly seen at the apical side of the cells. The cytokines were only sparsely expressed in the stromal cells. There was no difference in the expression of TNF, TGFß1 and LIF between the different segments of the tube, while expression of IL-8, both in epithelium and stroma, was more pronounced in the ampullar region (P=0.0346 and P=0.0431 respectively) (Figure 1A and B, Table II).
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Following treatment with mifepristone, the expression of TNF
in epithelial cells of the proximal region of the Fallopian tube significantly increased compared to the same region in controls (P=0.0428) (Figure 1C and D
, Table III). Furthermore, after treatment with mifepristone the difference in IL-8 expression between the isthmic and ampullar region of the Fallopian tube observed in control samples disappeared. This seemed to be due to both an increase in staining in the isthmic region and a decrease in the ampullar region. However, these changes were too small to become statistically significant. Mifepristone had no effect on the expression of LIF and TGFß1 in stroma or epithelium in the tube (Figure 1D and E).
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Macrophages were identified in the stromal tissue of the different tubal segments by CD68 staining. The samples contained few macrophages with no significant difference in distribution or changes following treatment. The distribution did not correspond to the majority of cytokine staining. There was also staining in the muscular wall of blood vessels, which was not affected by mifepristone.
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Discussion |
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In the present study, we have shown that the cytokines TNF
, TGFß1, LIF and IL-8 are present in the human Fallopian tube on cycle days LH+3 to LH+5. These cytokines were expressed both in the epithelial and stromal cells of the Fallopian tube. Furthermore, treatment with mifepristone altered the expression of IL8 and TNF while the expression of TGFß and LIF was unaffected.
There was a higher expression of IL-8 in the distal part than in the proximal part located both to the stromal and the epithelial cells in controls. This difference was observed in both the epithelial and stromal cells, which is consistent with earlier findings (Palter et al., 2001). The segmental variation of IL-8 in the tube has been suggested to be due to the differences in the populations of epithelial cells present in each location with a maximal secretory activity in the isthmic region and a higher degree of ciliated cells in the ampullar region (Palter et al., 2001).
Choriodecidual cells in culture produce substantial amounts of IL-8, and its release is inhibited by progesterone and stimulated by mifepristone (Kelly et al., 1992). Interestingly, treatment with mifepristone made the spatially dependent expression of IL-8 disappear.
In the human endometrium, treatment with a single dose of 200 mg of mifepristone on day LH+2 has a profound effect on endometrial morphological development during the mid-luteal phase (Gemzell-Danielsson, 1994). No effect could be seen following the same treatment on the morphology of the Fallopian tube. Tissue-specific effects of mifepristone have previously been demonstrated (Slayden and Brenner, 1994). In female macaque monkeys, mifepristone treatment blocked progesterone action and allowed estradiol to maintain oviductal wet weight and a ciliated-secretory state of differentiation similar to those found after estradiol treatment alone (Slayden and Brenner, 1994). Moreover, treatment with the antiprogestin ZK 137 316 was shown to block the antagonistic effects of progesterone on estrogen-dependent differentiation of the oviduct in a dose-dependent fashion. Demonstrating diverse action of the antiprogestin in the oviduct and endometrium, ZK 137 316 treatment also resulted in a dose-dependent atrophy of the endometrium (Slayden et al., 1998).
When given immediately after ovulation, mifepristone can be used as an effective contraceptive method (Gemzell-Danielsson et al., 1993; Hapangama et al., 2001), probably acting through an inhibitory effect on endometrial receptivity (Gemzell-Danielsson et al., 1994). The effect of early luteal phase treatment of mifepristone in the endometrium is most pronounced at approximately cycle days LH+6 to LH+8. On day LH+4, these changes are not yet fully apparent (Cameron et al., 1997). The expression of ER and PR in oviduct is segment-different and cycle-dependent (Amso et al., 1994; Christow et al., 2002). An increase in PR levels following mifepristone was already significant on days LH+4 to LH+6 (Christow et al., 2002).
Administration of mifepristone to monkeys at the post-ovulatory stage delays embryo development in the morula-to-blastocyst transition stage in vitro (Ghosh et al., 1997) but has no direct effect on embryo development in vitro (Wolf et al., 1990). In rats, post-coital mifepristone causes accelerated oviductal transport of the embryo and delays embryo development beyond the morula stage and postpones endometrial receptivity (Psychoyos and Prapas, 1987). Blastocysts transferred from mifepristone-treated rats to untreated pseudopregnant recipients implanted although at a lower rate than controls. Blastocysts transferred from control pregnant rats to mifepristone treated recipients failed to implant (Roblero and Croxatto, 1991).
Cytokines act as mediators of steroid hormones. There is an increasing number of reports demonstrating that cytokines can act as mediators of embryo and maternal tract communication. It has been shown that embryos during the early developmental stages express the receptors for the cytokines studied here.
The present study has shown that treatment with mifepristone in the early luteal phase increased the expression of TNF in epithelium of the proximal region of the Fallopian tube. mRNA encoding the TNF receptor is expressed at various stages in the human preimplantation embryo (Sharkey et al., 1995). In the mouse, it has been demonstrated that TNF binds to mouse blastocyst inner cell mass (ICM) (Pampfer et al., 1994). Exposure to TNF resulted in a significant reduction in the average number of cells, increased apoptosis in the ICM, and decreased the ability of embryos to differentiate after implantation (Wuu et al., 1999). The increased expression of TNF in the Fallopian tube after mifepristone treatment could negatively influence the development of the embryo. This could be an additional contraceptive effect of mifepristone, besides the negative influence on ovulation and endometrial development.
It is well known that cytokines and growth factors interact with each other to increase or decrease secretion and production in various systems. TNF stimulates the production of IL-8 in human endometrium in vitro (Arici et al., 1993). In our study, mifepristone increased TNF expression in the isthmic epithelial cells, where we also observed a slight, although not significant, increase in IL-8. Our study does not show whether the effect of mifepristone on IL-8 is a direct effect or an indirect effect via TNF.
LIF receptor mRNA has been found on human oocytes and blastocysts in a stage-dependent manner (Senturk and Arici, 1998). Both TGFß1 type I and type II receptors are detected in human embryos from 1-cell to the blastocyst stage (Österlund and Fried, 2000). However, mifepristone had no effect on the expression of TGFß1 and LIF in the Fallopian tube.
In a mouse model, ovariectomy does not reduce the level of TGFß1 mRNA in the ampullar and isthmic regions of the oviduct (Dalton et al., 1994). LIF mRNA is expressed in human Fallopian tube with only slight variation during the menstrual cycle. Furthermore, estradiol and progesterone did not modulate LIF expression in oviductal epithelial or stromal cells in culture, whereas IL-1, TNF and TGFß1 enhanced LIF expression in both epithelial and stromal cells (Keltz et al., 1996). Early luteal phase administration of mifepristone decreased the expression of LIF in the mid-secretory phase endometrium (LH+6) but had no effect on day LH+4 (Cameron et al., 1997).
In conclusion, we show that IL-8, TNF, TGFß and LIF are expressed in the human Fallopian tube, and that the expression of IL8 and TNF is directly or indirectly regulated by progesterone. Cytokines from the maternal tract bind to their corresponding receptors in the embryo and could thus influence early preimplantation embryo development. We suggest that the effect of mifepristone on the distribution and expression of TNF and IL-8 may adversely affect early embryo development and inhibit implantation.
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Acknowledgements |
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The authors would like to thank research nurses Lena Elffors-Söderlund and Margareta Hellborg for taking good care of the patients, and Berit Ståbi for excellent technical assistance. The study was supported by grants from the Swedish Medical Research Council (6392), The Swedish society of Medicine, Goljes Foundation and the Karolinska Institute Research Funds.
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Submitted on February 6, 2004; accepted on March 26, 2004.
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