Human Reproduction

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Human Reproduction, Vol. 16, No. 9, 1797-1801, September 2001
© 2001 European Society of Human Reproduction and Embryology

Reactive oxygen species stimulate prostaglandin F2 production in human endometrial stromal cells in vitro

Norihiro Sugino^,1, Ayako Karube-Harada, Shiro Kashida, Shuji Takiguchi and Hiroshi Kato

Department of Obstetrics and Gynecology, Yamaguchi University School of Medicine, Minamikogushi 1–1–1, Ube 755-8505, Japan

	Abstract

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BACKGROUND: The present study was undertaken to investigate the effect of reactive oxygen species on prostaglandin F2 (PGF2) production by human endometrial stromal cells (ESC). METHODS AND RESULTS: Isolated ESC were incubated with hydrogen peroxide, which induces lipid peroxidation. Hydrogen peroxide increased both intracellular and medium concentrations of PGF2 (P < 0.01). A time course study showed that hydrogen peroxide significantly increased PGF2 concentrations in the medium after 6 h incubation (P < 0.01), after which no further increase was observed. To study whether the increase in PGF2 production caused by hydrogen peroxide was mediated by cyclooxygenase, ESC were incubated with indomethacin (0.5 µg/ml), an inhibitor of cyclooxygenase, in the presence of hydrogen peroxide. Indomethacin significantly blocked the increases in PGF2 production caused by hydrogen peroxide (P < 0.01). Hydrogen peroxide also increased PGF2 production by decidualized ESC (P < 0.01), induced by the incubation with medroxyprogesterone acetate (10^–6 mol/l) and oestradiol (10^–8 mol/l). CONCLUSIONS: Reactive oxygen species stimulate PGF2 production in ESC, suggesting that they might influence endometrial function by regulating PGF2 production.

Key words: endometrial stromal cell/human/hydrogen peroxide/prostaglandin F2/reactive oxygen species

	Introduction

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It has been reported that both reactive oxygen species (ROS) and superoxide dismutase (SOD), an enzyme that scavenges superoxide ions, play important roles in the regulation of endometrial function (Narimoto et al., 1990; Sugino et al., 1996, 2000a,b). Reactive oxygen species are increased in the late secretory phase endometrium, prior to menstruation, suggesting that ROS may be involved in endometrial shedding by causing tissue damage (Sugino et al., 1996). It has also been reported that prostaglandin F2 (PGF2) is locally produced in the endometrium and regulates the endometrial function (Baird et al., 1996; Novaro et al., 1996). The level of PGF2 in the human endometrium increases toward the late secretory phase and is the highest at menstruation (Downie et al., 1974; Ishihara et al., 1986). It has therefore been well accepted that PGF2 is involved in endometrial shedding by its vasoconstriction effect (Baird et al., 1996). It is noted that ROS can produce substances that have biological activities (Morrow et al., 1990; Wu et al., 1992; Schenk et al., 1994; Pratico and FitzGerald, 1996). Since there are several reports in other tissues that prostaglandin synthesis can be stimulated by ROS (Hemler et al., 1979; Hemler and Lands, 1980; Cherouny et al., 1988; Karayalcin et al., 1990; Kodaman et al., 1994; Feng et al., 1995), functions of ROS in the endometrium may be mediated through PGF2 production. Thus, it is of interest to know whether ROS can influence human endometrial function by regulating PGF2 production.

PGF2 can be produced by endometrial stromal cells (Lumsden et al., 1984; Chen et al., 1995; Skarzynski et al., 2000), and cyclooxygenase, the rate-limiting enzyme in the biosynthesis of prostaglandins, is also expressed in endometrial stromal cells (Han et al., 1996; Jones et al., 1997). We recently reported close association of ROS or SOD with PGF2 in decidual cells (Sugino et al., 2000b). Therefore, we focused on endometrial stromal cells and studied whether ROS could stimulate PGF2 production to influence endometrial function.

	Materials and methods

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This project was reviewed and approved by the committee of investigations involving human subjects of Yamaguchi University School of Medicine. Informed consent from the patient was obtained before collection of any tissue samples for this study.

Materials
Phenol Red-free Dulbecco's modified Eagle's medium (DMEM) and glutamine were purchased from ICN Biomedicals Inc. (Aurora, OH, USA). Streptomycin, penicillin and trypsin-EDTA were from Life Technologies Inc. (Grand Island, NY, USA). Collagenase, indomethacin, 6--methyl-17OH-hydroxyprogesterone acetate (MPA), and oestradiol were from Sigma Chemical Co. (St Louis, MO, USA). Hydrogen peroxide was from Wako Pure Chemical Industries Ltd (Osaka, Japan). High performance liquid chromatography grade acetonitrile was obtained from Nacalai Tesque Co Ltd (Kyoto, Japan). Tissue flasks, culture plates and nylon mesh were from Becton Dickinson Co. (Franklin Lakes, NJ, USA).

Endometrial stromal cell isolation
Human endometrium was obtained at hysterectomy from normally cycling premenopausal women, aged 40–42 years, who underwent surgery for myoma uteri. Endometrial samples were histologically diagnosed as late proliferative phase according to the criteria of Noyes et al. (Noyes et al., 1950). Tissue samples were washed with Phenol Red-free DMEM containing 200 mmol/l glutamine, 100 mg/ml streptomycin and 50 IU/ml penicillin, and minced into small pieces of <1 mm³. Endometrial stromal cells were isolated as reported previously (Sugino et al., 2000a). In brief, after the enzymatic digestion of minced tissues with 0.2% collagenase in a shaking water bath for 2 h at 37°C, stromal cells were separated by filtration through a 70 µm nylon mesh. The filtrates were washed three times, and the number of viable cells was counted by Trypan Blue dye exclusion. The homogeneity of the stromal cell preparation was verified by immunocytochemistry for the stromal cell-reacting antibody (vimentin) (data not shown). Cells were seeded at 10⁵ cells/cm² in 75 cm² tissue culture flasks and incubated in Phenol Red-free DMEM containing glutamine, antibiotics and 10% dextran-coated charcoal-stripped fetal calf serum (FCS) at 37°C, 95% air and 5% CO₂. At confluence, cells were treated with 1xtrypsin-EDTA and subcultured into 25 cm² tissue culture flasks. At ~80% confluence after the first passage, the cell culture medium was changed to the treatment medium.

Cell culture
To examine the effect of lipid peroxidation on PGF2 production by endometrial stromal cells, cells were incubated with hydrogen peroxide (10, 50, 100, 200 µmol/l) in the medium (Phenol Red-free and serum-free DMEM supplemented with glutamine and antibiotics) for 6 h at 37°C, 95% air and 5% CO₂.

To study the time course, endometrial stromal cells were incubated with hydrogen peroxide (200 µmol/l) for 3, 6, or 24 h under the same condition as described above.

To examine whether hydrogen peroxide is also effective in decidualized endometrial stromal cells, endometrial stromal cells were decidualized by incubation with phenol red-free DMEM supplemented with glutamine, antibiotics, 2% stripped FCS, MPA (10^–6 mmol/l) and oestradiol (10^–8 mmol/l) for 18 days at 37°C, 95% air and 5% CO₂, and then incubated with hydrogen peroxide (200 µmol/l) for 6 h under the same condition as described above. Decidualization was confirmed by the mRNA expression of insulin-like growth factor-binding protein-1 (IGFBP-1), which is a specific marker of decidualization (Giudice et al., 1992; Kim et al., 1998; Sugino et al., 2000a).

To study whether the effect of hydrogen peroxide on PGF2 production is mediated by cyclooxygenase, endometrial stromal cells were incubated with indomethacin (0.5 µg/ml), an inhibitor of cyclooxygenase, in the presence of hydrogen peroxide (200 µmol/l) for 6 h under the same condition as described above. After cell incubation, PGF2 concentrations in the medium and cells were determined. A single incubation was performed in triplicate on cells from a single hysterectomy sample. The samples from three individuals were used in a single experiment. Therefore, three different incubations were performed in a single experiment. To examine the effect of hydrogen peroxide and/or indomethacin on cell viability, cells were seeded at 10⁵ cells/ml into each well of a 24-well culture plate and incubated. After incubation, cell viability was tested by the Trypan Blue dye exclusion method. Three different incubations were performed in triplicate. Hydrogen peroxide (200 µmol/l) and/or indomethacin had no effect on cell viability after 6 h incubation: control: 75.3 ± 3.3%, H₂O₂: 73.5 ± 3.7%, indomethacin: 72.9 ± 2.3%, H₂O₂ + indomethacin: 71.3 ± 5.3%; mean ± SEM of three different incubations.

PGF2 assay
After incubation, the cells were washed twice, resuspended in PBS (0.01 mmol/l, pH 3.0) and sonicated. Prostaglandins were extracted as reported previously (Sugino et al., 2000b) based on a previously reported method (Olofsson et al., 1990). In brief, sonicated samples and the medium were applied to a C18-LRC solid phase extraction cartridge (Bond-Elut, Varian Co., Harbor City, CA, USA), and the cartridge was rinsed with distilled water and 10% acetonitrile. Prostaglandins were then eluted with methanol and evaporated under nitrogen. The dried extract was dissolved in ethanol and the kit assay solution, and PGF2 concentrations were determined by a PGF2 enzyme immunoassay kit (Assay Designs, Inc., Ann Arbor, MI, USA). The sensitivity of the assay was 4.6 pg/ml. The intra- and inter-assay coefficients of variation were 7.8 and 7.0% respectively. The results were expressed as ng PGF2 per mg protein for cellular concentrations and as ng per ml for medium concentrations. Protein concentrations in the sonicated samples were determined by the method described by Lowry et al. (Lowry et al., 1951).

Statistical analysis
Data were examined by analysis of variance (ANOVA) and Duncan's new multiple range test. Where appropriate, Student's t-test was employed. Differences were considered significant at P < 0.05.

	Results

Top Abstract Introduction Materials and methods Results Discussion Acknowledgements References

 
To examine the effect of lipid peroxidation on PGF2 production, isolated endometrial stromal cells were incubated with hydrogen peroxide. Hydrogen peroxide appeared to increase both intracellular and medium concentrations of PGF2 in a dose-dependent manner (Figure 1). A time course study showed that hydrogen peroxide (200 µmol/l) significantly (P < 0.01) increased PGF2 concentrations in the medium after 6 h incubation (Figure 2) but did not increase it further after 24 h. We next examined whether decidualization affected the responsiveness of endometrial stromal cells to hydrogen peroxide. Hydrogen peroxide also significantly (P < 0.01) increased intracellular and medium concentrations of PGF2 in the decidualized endometrial stromal cell (Figure 3). To study whether the increase in PGF2 production caused by hydrogen peroxide is mediated by cyclooxygenase, endometrial stromal cells were treated with indomethacin (0.5 µg/ml), an inhibitor of cyclooxygenase, in the presence or absence of hydrogen peroxide (200 µmol/l). As shown in Figure 4, hydrogen peroxide significantly (P < 0.01) increased intracellular and medium concentrations of PGF2, and indomethacin significantly (P < 0.05 and P < 0.01) blocked the increases in PGF2 production caused by hydrogen peroxide. Indomethacin alone caused no significant effect (Figure 4).

View larger version (28K): [in this window] [in a new window]   Figure 1. Effects of hydrogen peroxide on PGF2 production by human endometrial stromal cells. Isolated endometrial stromal cells were incubated with hydrogen peroxide (H2O2; 10, 50, 100, 200 µmol/l) for 6 h at 37°C, 95% O2 and 5% CO2. (A) PGF2 concentrations in the medium and (B) PGF2 content in the cell. A single incubation was performed in triplicate on cells from a single hysterectomy sample. The samples from three individuals were used in a single experiment. Therefore, three different incubations were performed in a single experiment. An incubation-related mean was calculated for each incubation and the data are mean ± SEM of three incubation-related means. aP < 0.01 and bP < 0.05 versus control.

 

View larger version (16K): [in this window] [in a new window]   Figure 2. Time course of PGF2 release by endometrial stromal cells treated with hydrogen peroxide. Endometrial stromal cells were incubated with hydrogen peroxide (200 µmol/l) for 3, 6 or 24 h. PGF2 concentrations in the medium were determined. Values are mean ± SEM of three incubations with different samples as described in the legend to Figure 1. Hydrogen peroxide; •, control; , aP < 0.01 versus control.

 

View larger version (29K): [in this window] [in a new window]   Figure 3. Effects of hydrogen peroxide on PGF2 production in decidualized endometrial stromal cells. Endometrial stromal cells were decidualized by the incubation with MPA (10–6 mmol/l) and oestradiol (10–8 mmol/l) for 18 days, and then incubated with hydrogen peroxide (H2O2; 200 µmol/l) for 6 h. (A) PGF2 concentrations in the medium and (B) PGF2 content in the cell. Values are mean ± SEM of three incubations with different samples as described in the legend to Figure 1. aP < 0.01 versus control.

 

View larger version (25K): [in this window] [in a new window]   Figure 4. Inhibition of hydrogen peroxide-stimulated PGF2 production by indomethacin. Endometrial stromal cells were incubated with indomethacin (Indo; 0.5 µg/ml) in the presence of hydrogen peroxide (H2O2; 200 µmol/l) for 6 h. (A) PGF2 concentrations in the medium and (B) PGF2 content in the cell. Values are mean ± SEM of three incubations with different samples as described in the legend to Figure 1. (A) aP < 0.01 versus control,bP < 0.05 versus H2O2 + Indo, (B) aP < 0.01 versus control or H2O2 + Indo.

 

	Discussion

Top Abstract Introduction Materials and methods Results Discussion Acknowledgements References

 
It has been reported that ROS and SOD play important roles in the regulation of endometrial function (Narimoto et al., 1990; Sugino et al., 1996, 2000a,b). The role of ROS in human endometrial function has not been fully clarified. We previously suggested that accumulation of ROS may be involved in the shedding of the endometrium by causing tissue damage (Sugino et al., 1996). Recently, much attention has been focused on the observation that ROS can produce substances that have biological activities (Morrow et al., 1990; Wu et al., 1992; Schenk et al., 1994; Pratico and FitzGerald, 1996). The present study has demonstrated that ROS stimulate PGF2 production in human endometrial stromal cells. This is consistent with previous reports in other tissues that prostaglandins synthesis can be stimulated by ROS (Hemler et al., 1979; Hemler and Lands, 1980; Cherouny et al., 1988; Karayalcin et al., 1990; Kodaman et al., 1994; Feng et al., 1995). It is well accepted that PGF2 is locally produced in the endometrium and regulates endometrial function (Baird et al., 1996; Novaro et al., 1996). PGF2 has been implicated as a vasoconstrictor in the modulation of blood vessel tone prior to and during menstruation and is responsible for endometrial shedding (Baird et al., 1996). In fact, the increase in PGF2 concentrations and lipid peroxide concentrations was observed in the late secretory human endometrium, just before menstruation (Downie et al., 1974; Ishihara et al., 1986; Sugino et al., 1996). Secretory endometrium has also been reported to release more PGF2 than proliferative endometrium (Abel and Baird, 1980). Thus, the present study suggests that ROS influence human endometrial function by regulating PGF2 production.

In contrast, it has been reported that synthetic capacity of prostaglandins is very low after conception in human decidua (Maathuis and Kelly, 1978; Ishihara et al., 1986). We also found that ROS were low in the decidua of early pregnancy (Sugino et al., 1996). These findings are in agreement with the present result and seem reasonable for the maintenance of pregnancy. In spontaneous abortion, expulsion of the uterine content occurs to terminate pregnancy, usually accompanied by uterine contraction. However, in the case of the missed abortion, dead products of conception are retained in the uterus without bleeding for several weeks. Thus, the exact mechanism responsible for spontaneous expulsion is not precisely clarified. We recently reported that the concentrations of lipid peroxide and PGF2 of the decidua of missed abortion were the same as those of normal pregnancy and much lower than those of incomplete abortion with uterine contraction and uterine bleeding (Sugino et al., 2000b). Therefore, increased lipid peroxides in the decidua could be responsible for the increased PGF2 production, eventually to induce uterine contraction and expulsion of the uterine content (Cherouny et al., 1988; Norman et al., 1991).

In conclusion, the present study has shown that ROS might influence endometrial function by regulating PGF2 production in human endometrial stromal cells.

	Acknowledgements

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This work was supported in part by a grant from the UBE Foundation and Grant-in-Aid 11671623, 13671721 from the Ministry of Education, Science, and Culture, Japan.

	Notes

 
¹ To whom correspondence should be addressed. E-mail: obgyn{at}po.cc.yamaguchi-u.ac.jp

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Submitted on November 14, 2000; accepted on June 5, 2001.

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