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Interleukin-1ß Induces Cyclooxygenase-2 Gene Expression in Cultured Endometrial Stromal Cells

Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Reproductive Endocrinology, and the Department of Internal Medicine, Division of Hematology (K.K.W.), University of Texas Health Science Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Jaou-Chen Huang, M.D., Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Texas Medical School, 6431 Fannin, MSB 3.036, Houston, Texas 77030. E-mail: jhuang{at}obg.med.uth.tmc.edu

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Increasing evidence indicates that PGs may play an obligatory role in blastocyst implantation. Cyclooxygenase (also known as PGH synthase) isozymes 1 and 2 catalyze the rate-limiting steps in the biosynthesis of PGs. The ubiquitous cyclooxygenase-1 (COX-1) subserves housekeeping functions, whereas the inducible cyclooxygenase-2 (COX-2) is expressed by limited cell types and tightly controlled. Here we report the induction of COX-2 gene expression by interleukin-1ß (IL-1ß) in cultured human endometrial stromal cells.

COX-2 activity was induced by IL-1ß (1 ng/mL); conversion of exogenous arachidonic acid to PGF₂ increased from 2.6 ± 0.6 ng/well (mean ± SEM; n = 6) to 22.2 ± 5.6 ng, but was completely blocked (2.8 ± 0.7 ng/well) by NS-398, a specific COX-2 inhibitor. Undetectable in quiescent stromal cells, messenger ribonucleic acid for COX-2 was induced 30 min after IL-1ß treatment, reached a maximum at 4 h, and decreased after 15 h. Protein synthesis was not required for induction of the COX-2 gene, as it was blocked by actinomycin D but not by cycloheximide. The 70-kDa COX-2 protein was not detected in quiescent cells, became detectable 6 h after IL-1ß treatment, and remained detectable even after 15 h. IL-1ß (0.1–100 ng/mL) increased the luciferase activity in promoterless luciferase reporter containing the 900-bp 5'-flanking sequence (-891 to +9) of the COX-2 gene in a dose-dependent manner, with an ED₅₀ of 0.1–1 ng/mL.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
PGs, LEUKOTRIENES, endothelins, and nitric oxide are vasoactive substances in the endometrium (1). The endometrial response to the implanting blastocyst shares many features similar to those of PG-mediated inflammatory reactions, such as dilatation of microvessels and increased capillary permeability (2). In many species, PG production is increased during the periimplantation period and at the implantation sites (2). Higher concentrations of PGF₂ are present in the human endometrium during the midluteal phase (3). Cyclooxygenase (COX) converts arachidonic acid (AA) to PGG and PGH, the rate-limiting step in PG biosynthesis. COX-1 is constitutively expressed in most mammalian cells (4), but COX-2 is expressed in only certain cell types, such as fibroblasts, endothelial cells, and smooth muscle cells (5). The COX-2 gene is induced by mitogens (5), cytokines (6), serum (7), and hCG (8).

Recent evidence indicates that cytokines may be involved in blastocyst implantation (2). Interleukin-1 (IL-1) is postulated to mediate the communication between the blastocyst and the endometrium, both of which express IL-1 (9). Throughout the menstrual cycle, the endometrium expresses IL-1, IL-1ß, IL-1 receptor, and IL-1 receptor antagonist (IL-1ra) (10, 11). Secretion of IL-1, IL-1ß, and IL-1ra into the endometrial cavity changes according to the levels of steroid hormones, with IL-1ß reaching its peak around the time of implantation (12).

In rat endometrium, IL-1 increases COX activity and PG production in stromal cells (13) and induces COX-2 expression and PGE₂ production in epithelial cells. With human endometrium, IL-1ß stimulates increased PGE₂ synthesis in decidualized stromal cells (14) and epithelial cells (15). hCG up-regulates COX-2 gene and promotes decidualization in stromal cells (16). Furthermore, newly differentiated luminal epithelial cells at the implantation site express COX-2 (7).

Although COX-2 messenger ribonucleic acid (mRNA) has been demonstrated in human endometrium (17), its regulation remained unclear. Therefore, we examined the effects of IL-1ß on the expression of COX-2 gene in cultured human endometrial stromal cells.

	Materials and Methods

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Unless specified otherwise, all chemicals were purchased from Sigma Chemical Co. (St. Louis, MO). Phenol red-free DMEM-Ham’s F-12 (DMEM/F12) was purchased from Life Technologies (Grand Island, NY), collagenase was purchased from Worthington Biochemical Corp. (Freehold, NJ), and IL-1ß and IL-1ra were obtained from R&D Systems (Minneapolis, MN). Antibody against COX-2, NS-398, and enzyme immunoassay kits for PGF₂ were purchased from Cayman Chemicals (Ann Arbor, MI). The PGF₂ assay had a minimum detection limit of 15.6 pg/mL, less than 0.1% cross-reactivity with PGE₂, and less than 10% intra- and interassay coefficients of variability. The growth medium was DMEM/F12 supplemented with 10% fetal calf serum. The serum-free medium was DMEM/F12 supplemented with insulin (0.25 U/mL), BSA (1 mg/mL), transferrin (5 µg/mL), penicillin (10 U/mL), and streptomycin (10 µg/mL).

Stromal cell culture

Luteal phase endometrial tissues were obtained from women undergoing gynecological procedures for benign nonendometrial disorders. The phase of the menstrual cycle was determined by histological dating of the endometrium (18). The study was approved by the committee for the protection of human subjects, University of Texas Health Science Center (Houston, TX). The stromal cells were prepared as described by Satyaswaroop et al. (19), with some modifications. Briefly, the endometrium was collected into phosphate-buffered saline solution (PBS), washed until clean, cut into 2-mm pieces, and digested with collagenase (4000 U/mL). After digestion, the cell suspension was filtered through 80-µm pore size nylon mesh. The filtrate was then placed in a T-75 flask and incubated at 37 C in air with 5% CO₂ for 30 min. The supernatant was discarded, and the adherent stromal cells were maintained in growth medium, with a medium change every 3–4 days. When the cells reached confluence, they were subcultured in a 10-cm plate or a six-well plate using 10 or 1 mL growth medium, respectively. Trypan blue exclusion test showed that more than 90% of the harvested cells were viable (20). Ninety-five percent of the cells stained positive for vimentin and negative for cytokeratin. The cells produced PRL when stimulated by progesterone.

Conversion of exogenous AA to eicosanoids

The conversion of AA to PG was studied as previously described (21, 22). Subcultured stromal cells (100,000 cells/well) were maintained in six-well plates (1 mL/well) until 70% confluence was reached. After serum starvation for 24 h, the cells were stimulated with IL-1ß (1 ng/mL) or PBS for 6 h. AA (10 µmol/L) in 100% ethanol was added at the end of the 6-h incubation. The media was collected 30 min later and stored at -70 C, and subsequently, PGF₂ was determined in duplicate. We added NS-398 30 min before AA to block COX-2 activity. Ethanol in the medium did not exceed 0.2%. In a separate experiment, IL-1ra (10 pg/mL) or dexamethasone (DEX; 10 µmol/L) was added 30 min before IL-1ß.

Northern analysis

Subcultured stromal cells in 10-cm plates were maintained in growth medium until 90% confluence was reached. After serum starvation for 24 h, the cells were stimulated with IL-1ß (1 ng/mL) in the presence or absence of cycloheximide (100 µmol/L) or actinomycin D (1 µmol/L). Total RNA was extracted according to the method of Chomczynski and Sacchi (23). Twenty-five to 30 µg RNA were separated by 1.2% formaldehyde agarose gel and transferred to a nylon membrane. The membrane was first hybridized with a ³²P-labeled probe from the 1.5-kilobase PstI/NotI fragment of the COX-2 complementary DNA (6). The membrane was then stripped and hybridized with a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) probe. The message for COX-2 was expressed as the ratio of COX-2 to GAPDH mRNA signals, determined by PhosphorImager using ImageQuant software (Molecular Dynamics, Sunnyvale, CA).

Western analysis

Subcultured stromal cells were maintained (see above) and treated with IL-1ß (1 ng/mL) for various durations. Protein was extracted as previously described (24). Briefly, after two washes with ice-cold PBS, the cells were overlaid with boiling buffer (0.05 mol/L Tris-HCl, pH 7.4, and 1% SDS), and the lysate was stored at -70 C until assayed. The protein concentration was determined using a commercial kit (Micro BCA, Pierce Chemical Co., Rockford, IL). Aliquots of 40 µg protein from each sample were separated on 10% SDS-PAGE and electroblotted onto a nylon membrane. The COX-2 protein was detected using rabbit antihuman COX-2 polyclonal antibody and visualized using ECL system (Amersham, Aylesbury, UK).

Transient transfection

DNA preparation. Both promoterless luciferase reporter (pGL3) and p-simian virus-ß-galactosidase control vector (SVß-gal) were obtained from Promega Corp. (Madison, WI). A chimeric DNA 900-pGL3 was created by linking the 900-bp 5'-flanking region of COX-2 gene (-891 to +9 relative to transcription start site) (25) to pGL3. The plasmid DNA was prepared using commercial kits (Qiagen, Chatsworth, CA). The DNA concentration was determined by absorbance at 260 nm (DU-640, Beckman Instruments, Fullerton, CA).

Transient transfection. Transient transfection using cationic lipid was carried out under conditions that have been optimized in our laboratory (22, 26). Briefly, about 100,000 cells were subcultured in 6-well plates and maintained in growth medium for 48 h. Two hours before the transfection, the cells were given fresh DMEM/F12, then overlaid with DNA (2 µg 900-pGL3 and 0.4 µg SVß-gal) in 100 µL Lipofectamine (Life Technologies) and kept at 37 C in air with 5% CO₂ for 4 h. Thereafter, the cells were maintained in growth medium for 24 h. The cells received serum-free medium for an additional 16 h before the addition of IL-1ß (0.1–1 ng/mL). Promoterless vector and vector with SV-40 early promoter were used in all studies as negative and positive controls.

Preparation of cell lysate and assay for luciferase and ß-gal activities. After 4-h treatment, cell lysate was prepared according to manufacturer’s protocol (Promega) and stored at -70 C. The luciferase and ß-gal activities in 20 µL cell lysate were determined by a luminometer (Moonlight model 2010, Analytical Luminescence Laboratory, San Diego, CA), using commercial kits [Promega Co. and Clontech Laboratories (Palo Alto, CA), respectively]. The promoter activity was expressed as the ratio of luciferase to ß-gal activities.

Statistical analysis

The overall differences in each set of data was determined by one-way ANOVA, followed by post-hoc pairwise comparison using Bonferroni test. P < 0.05 or less was considered statistically significant.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Quiescent stromal cells converted AA to PGF₂ (mean ± SEM, 2.6 ± 0.6 ng/well; n = 6). After stimulation by IL-1ß for 6 h, PGF₂ production increased by 8.4-fold (22.2 ± 5.6 ng/well; P < 0.05). Pretreatment with NS-398 prevented such an increase (2.9 ± 0.7 ng/well; Fig. 1).

View larger version (29K): [in this window] [in a new window]   Figure 1. Effects of IL-1ß on the conversion of AA to PGF2 by the stromal cells. IL-1ß (1 ng/mL) significantly increased PGF2 production from 2.6 ± 0.6 ng/well (mean ± SEM; n = 6) to 22.2 ± 5.6 ng/well (P < 0.05). NS-398 (1 µmol/L) prevented the increase (2.9 ± 0.7 ng/well; P > 0.05).

2

View larger version (34K): [in this window] [in a new window]   Figure 2. Effects of IL-1ß, IL-1ra, and DEX on the conversion of AA to PGF2 by stromal cells. IL-1ß (1 ng/mL) significantly increased PGF2 from 44.8 ± 1.7 pg/well (mean ± SEM; n = 6) to 200.8 ± 21.4 pg/well (P < 0.05). Both IL-1ra (10 pg/mL) and DEX (10 µmol/L) blocked the increase (32.5 ± 2.6 and 86.6 ± 10.2 pg/well, respectively; P > 0.05).

View larger version (46K): [in this window] [in a new window]   Figure 3. a, A representative autoradiographic film showing the induction of mRNA for COX-2 by IL-1ß. Stromal cells were stimulated by IL-1ß (1 ng/mL) for various time periods. Total RNAs were extracted and probed for COX-2 and GAPDH. The mRNA for COX-2 was not detectable in quiescent cells, but peaked at 4 h. Actinomycin D (ActD; 1 µmol/L), but not cycloheximide (CHX; 100 µmol/L), suppressed the induction. The same experiment was repeated twice; similar results were obtained. b, Data based on PhosphorImager analysis. The corrected COX-2 message, expressed as the ratio of COX-2 to GAPDH mRNA signals, was not detectable at time zero, but became detectable (0.4) after 30 min. The message increased from 16.5 at 2 h to 23.3 at 4 h and decreased to 10.8 after 15 h. The COX-2 message was superinduced to 34.7 U by CHX; ActD completely blocked the induction.

View larger version (17K): [in this window] [in a new window]   Figure 4. Western analysis of COX-2 protein in stromal cells stimulated by IL-1ß. Stromal cells were stimulated by IL-1ß (1 ng/mL) for various time periods. Aliquots of 40 µg protein were separated on SDS-PAGE and electroblotted to a nylon membrane. The COX-2 protein (70 kDa; arrow) was detected by an antibody against human COX-2.

View larger version (54K): [in this window] [in a new window]   Figure 5. Effect of IL-1ß on the promoter activity of COX-2 gene. Stromal cells were cotransfected with 900-pGL3 and SV-ß-gal (see text) and stimulated by IL-1ß (0.01–100 ng/mL). The promoter activity was expressed as the ratio of luciferase activity to ß-gal activity. The concentration of IL-1ß required to produce a significant difference from the control value was 0.1 ng/mL; the ED50 was between 0.1–1 ng/mL. There was no difference among IL-1ß doses of 1, 10, and 100 ng/mL.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

In quiescent stromal cells, COX-1 activity is responsible for the basal PG synthesis. Thus, regulation of the expression of COX-2 is key to the control of PG synthesis. We confirmed that COX-2 gene is a primary response gene inducible in human endometrial stromal cells. Additionally, IL-1ß may mobilize AA from membrane phospholipids to provide the substrate for COX (29). The 900-bp 5'-flanking sequence of the COX-2 gene was sufficient to respond to IL-1ß, acting through its receptor, as suggested by the dose-response curve of IL-1ß. Our ED₅₀ for stromal cells (0.1–1 ng/mL) is similar to that reported for human articular chondrocytes (30).

There are two copies of nuclear factor-B (NF-B) and NF-IL-6 response elements in the sequence used for the transfection study (25). Because IL-1ß also induces IL-6 expression in human endometrial stromal cells (31), NF-B and/or NF-IL-6 could mediate the effects of IL-1ß. Deletion analysis is required for a full explanation.

Unlike NS-398, which induces structural changes in COX-2 (32), DEX inhibits the gene transcription (5, 33, 34) through inhibitor protein IBs. Preincubation for 30 min did not completely suppress COX-2 induction. A longer preincubation and/or higher concentration may be required.

In conclusion, IL-ß induces the gene expression of COX-2 in human endometrial stromal cells.

	Acknowledgments

 
The authors thank Mary Carson for typing the manuscript, and Jun Yang for technical assistance.

Received August 7, 1997.

Revised October 22, 1997.

Accepted October 27, 1997.

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Top Abstract Introduction Materials and Methods Results Discussion References

 

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