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-Induced Interleukin-8 (IL-8) Expression in Endometriotic Stromal Cells, Probably through Nuclear Factor-
B Activation: Gonadotropin-Releasing Hormone Agonist Treatment Reduced IL-8 Expression
Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago 683-8504, Japan
Address all correspondence and requests for reprints to: Yasuko Sakamoto, M.D., Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago 683-8504, Japan. E-mail: sakayasu{at}grape.med.tottori-u.ac.jp.
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Abstract |
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promoted proliferation of endometriotic stromal cells by inducing IL-8 gene and protein expression. We hypothesize that TNF may induce IL-8 production in endometriotic cells through nuclear factor-
B (NF-B) activation. Western blot analyses and electrophoretic mobility shift assays revealed that incubation with TNF induced the expression of phosphorylated inhibitor B (p-IB) and activation of NF-B in endometriotic stromal cells. The NF-B inhibitor, N-tosyl-L-phenylalanine chloromethyl ketone, reduced TNF-induced IL-8 gene and protein expression. The medical treatment of endometriosis with GnRH agonist (GnRHa) has been shown to induce hypoestrogenemia and reduce the observable number of endometriotic implants. We compare the expression of IL-8 gene and protein in endometriotic stromal cells of patients treated with GnRHa and those of patients without treatment before laparoscopic cystectomy for endometrioma. The addition of TNF (0.1 ng/ml) significantly increased protein and gene expression of IL-8 in the cells of patients without GnRHa treatment, but this expression was not observed in the cells of patients with GnRHa. The addition of estradiol (E2; 10-7 M) enhanced the expression of IL-8. However, in the cells of patients who received GnRHa treatment, TNF and E2 did not show any significant effect. In endometriotic stromal cells without GnRHa treatment, TNF and E2 increased the expression of p-IB. In contrast, TNF and E2 had no significant effect on the expression of p-IB in cells that received GnRHa treatment. These findings demonstrate that NF-B activation is critical for TNF-induced IL-8 expression in endometriotic stromal cells. The current study showed for the first time that GnRHa treatment attenuated the expression of IL-8 by reducing TNF-induced NF-B activation. |
Introduction |
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We previously showed that IL-6, IL-8, and TNF are significantly elevated in the PF of women with endometriosis compared with that of women without endometriosis (1, 3). We found that PF levels of IL-8 significantly enhanced proliferation of stromal cells derived from ovarian endometriomas (3), suggesting that IL-8 may promote the progression of endometriosis. We also showed that TNF promoted the proliferation of endometriotic stromal cells by inducing IL-8 gene and protein expression (4).
Endometriosis is considered to be an inflammatory-like phenomenon. Inflammatory responses are now thought to be mediated by the activation of the transcription factor, nuclear factor-B (NF-B). NF-B can be activated by different stimuli, including proinflammatory cytokines. NF-B activation enhances the transcription of TNF, and TNF, in turn, is known to activate NF-B (5). TNF is known as a pluripotent mediator that promotes the production of other cytokines in various cells. Therefore, we hypothesize that TNF may induce IL-8 production in endometriotic cells through NF-B activation.
The dependence of endometriotic tissue on ovarian steroid hormones for its continuing growth, particularly estrogen, has resulted in medical treatments aimed at inducing the suppression of ovarian steroidogenesis. Continuous exposure of the GnRH agonist (GnRHa) results in desensitization or down-regulation of GnRH receptors with resultant reduction in circulating serum gonadotropin levels and inhibition of ovarian hormone production. The medical treatment of endometriosis with a GnRHa has been shown to reduce both the observable number of endometriotic implants and the frequency and severity of associated pain (6, 7, 8, 9, 10, 11). Thus, hypoestrogenemia induced by GnRHa accounts for its major effects. However, more detailed molecular mechanisms that exist between a low estrogen milieu and reduction of endometriotic lesions should be unveiled.
In this study we performed Western blot analysis and electrophoretic mobility shift assay (EMSA) to examine the role of NF-B during the induction of IL-8 gene and protein by TNF. In addition, we compared the expression of IL-8 gene and protein between the endometriosis-derived cells of patients treated with GnRHa and those of patients without GnRHa treatments before laparoscopic excision of endometrioma.
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Materials and Methods |
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With their informed consent, we recruited 22 women with endometriomas who had regular ovulatory cycles. Laparoscopic surgery was performed in 16 patients [in the follicular phase (n = 3) and the luteal phase (n = 13)] who did not receive preoperative GnRHa treatment. Six patients received GnRHa treatment for 4–6 months before laparoscopic surgery. Endometriosis was staged during the operation according to the revised American Society for Reproductive Medicine classification system. Among 16 patients who did not receive preoperative GnRHa treatment, 8 women had stage III disease, and 8 had stage IV disease. Among 6 patients who received GnRHa treatment, 2 women had stage III disease, and 4 had stage IV disease. The chocolate cyst linings of the ovaries were collected as the source of endometriotic tissue. The menstrual cycle phase was determined by measuring serum E2 and progesterone levels and by histological examination of endometrial tissues. Stromal cells were collected from endometriotic tissues according to the method of Osteen et al. (12) described in detail previously (3). We used stromal cells in a monolayer culture after the first passage.
The morphology and doubling time of the stromal cells derived from the chocolate cysts of patients with GnRHa treatment were similar to those of the cells of patients without GnRHa. To confirm the purification of the stromal cells, immunohistochemical analysis of isolated endometriotic stromal cells was performed using cytokeratin (DAKO Corp., Kyoto, Japan) as a marker of epithelial cells, vimentin (DAKO Corp.) as a marker of stromal cells, CD14 (Nichirei, Tokyo, Japan) as a marker of activated macrophages, and factor VIII (DAKO Corp.) as a marker of endothelial cells. The results showed that the purity of the stromal cells was more than 98%.
Western blot analysis
Endometriotic stromal cells were plated in a 100-mm dish, and cultures were allowed to proliferate until confluence, with exchange of medium containing 10% fetal bovine serum (FBS) every 48 h. The culture medium was exchanged to the phenol red-free medium without serum for 24 h. Then TNF (0.1 ng/ml; Genzyme Techne, Minneapolis, MN) was added to the medium for the indicated times in time course experiments. For experiments with E2, TNF (0.1 ng/ml) and estradiol [E2; 10-7 M; 1,3,5,(10)-estratrien-3, 17ß-diol; Sigma-Aldrich, St. Louis, MO] were added as described above, followed by incubation for 20 min. Incubation was terminated by aspiration of the medium, two washes with ice-cold PBS, and the addition of 80 µl lysis buffer (50 mM Tris-HCl, 125 mM NaCl, 0.1% Nonidet P-40, 5 mM ethylenediamine tetraacetic acid, 50 mM NaF, 0.1% phenylmethylsulfonylfluoride, and protease inhibitors). Equal quantities of cell lysates (50 µg) were separated by electrophoresis on a 10% gradient polyacrylamide gel and transferred to a polyvinylidene difluoride membrane (Millipore Corp., Bedford, MA). Proteins were visualized with antirabbit IgG coupled to horseradish peroxidase using enhanced chemiluminescence according to the manufacturer’s recommendation. The primary and secondary antiphosphorylated inhibitor B (anti-p-IB) antibodies used in this study were IB- (Ser32) antibody kit (Cell Signaling Technology, Inc., Beverly, MA). Western analyses were repeated at least three times, and the representative data are shown.
Preparation of nuclear extracts
Endometriotic stromal cells were plated in 100-mm culture dishes. Medium changes, preincubation, addition of TNF and E2, and incubation for 20 min were similarly performed as described above. Incubation was terminated by aspiration of the medium, two washes with ice-cold PBS, and addition of 100 µl hypotonic buffer A [10 mM HEPES-KOH (pH 7.8), 0.1 mM EDTA (pH 8.0), and 10 mM KCl]. The cells were then lysed in 0.1% Nonidet P-40 (Sigma-Aldrich) by vortexing for 5 sec and incubated for 5 min on ice. Nuclei were separated from the cytosol by centrifugation at 5000 rpm for 5 min and washed with 100 µl buffer A containing 0.1% Nonidet P-40. After transfer of the all supernatant, buffer C [50 mM HEPES-KOH (pH 7.8), 420 mM KCl, 0.1 mM EDTA (pH 8.0), 5 mM MgCl2, and 20% glycol] was added to the pellet, followed by vigorously vortexing for 15 sec and incubation for 30 min on ice. Then nuclear extracts were obtained from supernatants by centrifugation at 14,000 rpm for 10 min.
EMSA
The EMSA was performed using commercially available NF-B p50 gel-shift kits (Geneka Biotechnology, Inc., Québec, Canada). The double-stranded oligonucleotide containing the NF-B-binding site was end labeled using T4 polynucleotide kinase and [
-32P]ATP (AA0068, Amersham Biosciences, Tokyo, Japan). Nuclear protein extract (5 µg) was incubated with 1 x 105 cpm radiolabeled NF-B oligonucleotide at room temperature for 20 min in binding reaction buffer. The resulting complexes were separated on a 5% nondenaturing polyacrylamide gel in Tris-glycine-EDTA buffer. To test for specificity of NF-B binding, supershift analysis and competition experiments were carried out. For supershift analysis, nuclear extracts were incubated with 2 µg rabbit polyclonal antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) against the p50 and p65 subunits of NF-B complexes before incubation with the labeled probe. For competition experiments, a 100-fold excess of unlabeled oligonucleotide was incubated with nuclear extracts for 20 min at room temperature before the radiolabeled probe was added. Gels were dried, and autoradiography was performed at -80 C using Kodak Bio-Max film (Eastman Kodak Co., Rochester, NY).
Collection of supernatants of endometriotic stromal cells
Endometriotic stromal cells were plated in 24-well dishes at a concentration of 10 x 104 cells/well. After 24 h, the media were changed to remove unattached cells, and cultures were allowed to proliferate until confluence (24–72 h), with the medium containing 10% FBS exchanged every 24 h. Then cells were preincubated in phenol red-free medium without serum for 24 h at 37 C and received either medium alone or medium with TNF (0.1 ng/ml) for 24 h. The concentration of IL-8 in the culture supernatants was determined in duplicate using commercially available IL-8 ELISA kits (Genzyme Techne, Cambridge, MA). The minimum detectable level of IL-8 was 10 pg/ml. For experiments with E2, TNF (0.1 ng/ml) and E2 (10-9–10-7 M) were added and incubated for 24 h after the cells were preincubated in phenol red-free medium without serum for 24 h at 37 C.
Expression of IL-8 mRNA in endometriotic stromal cells
Endometriotic stromal cells were plated in 100-mm culture dishes at a concentration of 5–10 x 105 cells/dish. After 24-h incubation, the media were changed to remove unattached cells, and cultures were allowed to proliferate until confluence (3–5 d), with exchange of medium containing 10% FBS every 48 h. After the cells were preincubated in phenol red-free medium without serum for 24 h at 37 C, either medium alone or medium with TNF (0.1 ng/ml) or medium with TNF (0.1 ng/ml) and E2 (10-7 M) were added and incubated for 6 h. Total RNA was extracted by the guanidium thiocyanate method from the cells that had been treated in the described ways according to the manufacturer’s instructions (Isogen, Nippon Gene Co. Ltd., Tokyo, Japan). Total RNA (5 µg/sample) was size-fractionated by electrophoresis on 1% formaldehyde-agarose gels and transferred to Hybond-N+ membrane (Amersham Pharmacia Biotech). The partial-length human IL-8-specific cDNA (GenBank accession no. Y00787, nucleotide position 102–393) was labeled with [-32P]deoxy-CTP (AA0005, Amersham Biosciences), using a random labeling system (Amersham Pharmacia Biotech). The nylon membrane containing total RNA was incubated with the cDNA probe in hybridization buffer (Toyobo, Osaka, Japan) for 3 h at 65 C. Thereafter, the blot was washed once with 2x standard saline citrate and 0.1% sodium dodecyl sulfate for 20 min at 65 C and twice with 0.2x standard saline citrate and 0.1% sodium dodecyl sulfate for 20 min at 65 C. Autoradiography of the membranes was performed at -80 C using Kodak Bio-Max film (Eastman Kodak Co.). The length of film exposure to the blot is 2–3 h. The visualization of ethidium bromide-stained 28S ribosomal RNA subunits was used for normalization.
Effects of NF-B inhibitor on the expression of IL-8
Endometriotic stromal cells were plated in 24-well, 100-mm dishes as described above. After the cells were preincubated in phenol red-free medium without serum for 24 h at 37 C, N-tosyl-L-phenylalanine chloromethyl ketone (TPCK; 10-5 M; Sigma-Aldrich), an NF-B inhibitor, was added and incubated for 1 h. Then TNF (0.1 ng/ml) was added and incubated for 6 or 24 h. Northern blot analysis and ELISA were performed as described above.
Statistical analysis
Results were evaluated by one-way ANOVA, followed by Fisher’s protected least significant difference test. The data are expressed as the mean ± SE. P < 0.05 was accepted as indicating statistical significance.
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Results |
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B- in endometriotic stromal cells
The activation of NF-B is usually associated with phosphorylation of IB-, followed by its degradation by the proteasome and NF-B nuclear translocation. Therefore, to detect the activation of NF-B in endometriotic stromal cells during inducible expression of IL-8 by TNF, Western blot analysis were performed using an antibody for p-IB. Within 5–20 min of stimulation with TNF, p-IB was clearly observed (Fig. 1
). We also examined the effect of E2 on the activation of NF-B induced by TNF in the endometriotic stromal cells derived from patients with and without preoperative GnRHa treatment. In endometriotic stromal cells without GnRHa treatment, TNF increased the expression of p-IB, and treatment with E2 further enhanced its expression. However, TNF and E2 had no significant effect on the expression of p-IB in the cells receiving GnRHa treatment (Fig. 2).
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B complex in endometriotic stromal cells by EMSA
To verify that the phosphorylation of IB resulted in the activation of NF-B, an EMSA was performed using nuclear extracts of endometriotic stromal cells. In endometriotic stromal cells without GnRHa treatment, TNF induced an increase in NF-B complex, and treatment with E2 slightly increased NF-B DNA-binding activity in response to TNF (Fig. 3). The specificity of this reaction was confirmed by the addition of cold oligo-DNA, which eliminated the reactive band. Addition of antibodies directed against a 65,000 molecular weight subunit (p65) and antibodies against the 50,000 molecular weight subunit (p50) of NF-B induced supershift of the binding complexes.
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B activation
To further confirm the role of NF-B activation, the effect of TPCK, an NF-B inhibitor, on TNF-induced IL-8 protein and gene expression was assessed. TPCK prevents the degradation of the predominant inhibitory molecule, IB, and inhibits the translocation of NF-B into the nucleus. As we expected, pretreatment with TPCK reduced TNF-induced IL-8 protein production (Fig. 4A) as well as mRNA expression (Fig. 4B). The data confirm that TNF up-regulates IL-8 gene and protein expression in endometriotic cells via activation of NF-B.
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on IL-8 protein production in endometriotic stromal cells in patients with and without GnRHa treatment
We compared the levels of IL-8 protein production in endometriotic stromal cells between the supernatants of the endometriotic cells derived from patients with and without GnRHa treatment. Addition of TNF significantly increased IL-8 protein secretion in the stromal cells of patients who did not undergo preoperative GnRHa treatment (Fig. 5). The results were consistent with our prior study (4). In contrast, TNF did not significantly stimulate IL-8 protein production in the cells of patients who received preoperative GnRHa treatment.
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Addition of E2 enhanced IL-8 protein production induced by TNF in endometriotic stromal cells derived from patients without GnRHa treatment. This stimulatory effect of E2 was not observed in the cells of patients treated with GnRHa (Fig. 6). Northern blot analysis was performed to determine the effects of E2 on the levels of gene expression of IL-8 in endometriotic stromal cells. In the cells of patients without GnRHa treatment, TNF and E2 increased the expression of IL-8. On the other hand, TNF and E2 had no significant effect in the cells of patients treated with GnRHa (Fig. 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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induced IL-8 gene and protein expression in endometriotic stromal cells, probably through NF-B activation. We also showed that the addition of E2 significantly enhanced up-regulation of the IL-8 protein by TNF. Interestingly, stimulatory effects of TNF and E2 were only significant in endometriotic stromal cells derived from patients who did not undergo GnRHa treatment before laparoscopic surgery. It is known that phosphorylation of IB and its degradation are essential for liberation of NF-B from binding with IB (13). We demonstrated that TNF induced the expression of phosphorylated IB. Possible involvement of NF-B activation in TNF-inducible IL-8 up-regulation was verified in the experiments using an inhibitor for NF-B. To our knowledge this is the first report that IL-8 expression was attenuated in endometriotic cells after treatment with GnRHa. The data provide new evidence that hypoestrogenemia under GnRHa treatment may reduce the ability of cytokine production in endometriotic cells and thus lead to suppression of its progression. TNF and subsequent NF-B activation are key factors in this event. Arici et al. (14) reported that IL-8 is produced in the human endometrium in vivo, mainly in glandular cells, and that IL-8 induces the proliferation of endometrial stromal cells as a potential autocrine growth factor. We further demonstrated that IL-8 exerts its growth-promoting actions in normal endometrium as well as in endometriotic cells (3, 4). Two different cDNA-encoding human IL-8 receptors have been cloned, designated IL-8 receptor type A and type B. The gene expression of IL-8 receptor type A was confirmed in both endometrial and endometriotic cells (3). Because endometriotic tissues themselves produce IL-8, it is suggested that the growth and progression of endometriosis are mediated by both autocrine and paracrine pathways. Up-regulation of IL-8 receptors in endometriotic tissues has not been examined, and it is an interesting subject for future investigation.
GnRH is released from the hypothalamus in a pulsatile fashion, leading to the gonadotropic hormones, LH and FSH. Continuous exposure of pituitary receptors of GnRHa paradoxically down-regulates pituitary function, and LH and FSH levels decrease, leading to gonadal suppression. This, in turn, produces a fall in the E2 concentration, with resultant amenorrhea. In terms of efficacy, GnRHa is effective, reducing endometrial implants in 50–90% of patients and improving pain and physical findings in 75% of cases (6, 7, 8, 9, 10, 11). However, the molecular mechanism of estrogen action in endometriotic tissues has yet to be determined. The present results suggest that estrogen may enhance cytokine induction through modulating the cell signal transduction pathway.
In the present study the addition of E2 did not exert a significant effect on IL-8 production in endometriotic stromal cells derived from patients who received GnRHa treatment. One possible mechanism is that the levels of estrogen receptor may be reduced in the cells treated with GnRHa. Recently, Matsuzaki et al. (15) demonstrated that a long-term hypoestrogenic state induced by GnRHa decreased estrogen receptor- mRNA levels in endometriotic cysts by means of quantitative RT-PCR assay. These are few reports about the changes in gene and protein expression after GnRHa treatment for endometriosis. One study performed by Sharpe-Timms et al. (16) demonstrated that serum concentrations of tissue inhibitor of metalloproteinase-1, an important regulator of extracellular matrix, are attenuated in women with endometriosis and are restored after GnRHa therapy. Although their data were derived from inhalation of leuprolide aerosol, which is not conventional GnRHa therapy, they showed GnRHa treatment may have effects on secretion of tissue inhibitor of metalloproteinase-1 by endometriotic tissues (16).
Recent reports presented evidence that the degree of spontaneous apoptosis of eutopic and ectopic endometria was lower in women with endometriosis than in control subjects (17). The reports suggest that decreased susceptibility of endometrial tissues to apoptosis contributes to the pathogenesis of endometriosis. Imai et al. (18) extended this observation in some interesting aspects. They showed that lower sensitivity to apoptosis of endometrial cells of patients with endometriosis was ameliorated during exposure to GnRHa in culture (18). These results suggest a direct action of GnRHa on endometriotic cells other than leading to hypoestrogenemia after pituitary desensitization.
TNF was first identified as a cytokine secreted by endotoxin-activated macrophages that induced the necrosis of tumors (19). TNF is now known as a pluripotent mediator and angiogenic cytokine that promotes the production of other cytokines in various cells. We demonstrated here that TNF also promoted the production of cytokine in endometriotic tissue. TNF may play a central role as a key cytokine that agitates many other cytokines in the peritoneal cavity of endometriosis patients.
NF-B is normally bound to IB in cytosol; this binding prevents its movement into the nucleus (13). Proinflammatory stimuli induce the phosphorylation of IB, which releases NF-B. The latter translocates to the nucleus, where it induces the transcription of proinflammatory cytokines and the proteins/enzymes involved in reactive oxygen species generation. Thus, it modulates the molecular and cellular mechanisms involved in inflammation. We demonstrated here that NF-B activation has been involved in the induction of IL-8 in endometriotic tissues. Thus, NF-B plays an important role in the pathophysiology of endometriosis. We also showed for the first time that GnRHa treatment attenuates the expression of IL-8 by reducing TNF-induced NF-B activation. Therefore, novel therapeutic modalities for endometriosis targeting these molecules may be possible in the near future.
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Acknowledgments |
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Footnotes |
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B, nuclear factor-B; PF, peritoneal fluid; p-IB, phosphorylated inhibitor B; TPCK, N-tosyl-L-phenylalanine chloromethyl ketone. Received April 30, 2002.
Accepted October 23, 2002.
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References |
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promotes proliferation of endometriotic stromal cells by inducing interleukin-8 gene and protein expression. J Clin Endocrinol Metab 85:824–829B in cytokine gene regeneration. Am J Respir Cell Mol Biol 17:3–9B and steroid receptor-signaling pathways. Endocr Rev 20:435–459 and ß messenger ribonucleic acid levels in normal endometrium and ovarian endometriotic cysts using a real-time reverse transcription-polymerase chain reaction assay. Fertil Steril 74:753–759
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