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Localization in Tissues and Secretion of Eotaxin by Cells from Normal Endometrium and Endometriosis¹

Department of Obstetrics and Gynecology (D.H., K.D., R.R.G., D.W., L.K.) and Department of Pathology (K.S.), University of Tübingen, Germany; and Center for Reproductive Sciences (D.H., R.N.T.), Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143-0556

Address correspondence and requests for reprints to: Robert N. Taylor, M.D., Ph.D., Center for Reproductive Sciences, HSE 1689, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California 94143-0556.

	Abstract

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Our laboratories have focused recently on the production and localization of eotaxin, a C-C-chemokine of 8.4 kDa, whose major biological activity is the chemoattraction of eosinophils. Given evidence of autoimmune activity in the endometriosis syndrome, we hypothesized that eosinophil chemoattractants might be expressed in endometriosis. In histological sections, we observed eotaxin protein localized mainly in epithelial cells, with only very faint immunostaining in the surrounding stromal cells. Prominent eotaxin accumulation was noted in the luminal epithelium of secretory endometrium. Eotaxin distribution in endometriosis was similar to that seen in eutopic endometrium but with higher levels of eotaxin staining in the glandular epithelium. Peritoneal fluid concentrations of eotaxin were significantly higher in women with moderate or severe endometriosis than in women with minimal or mild endometriosis or no disease. The treatment of isolated human endometriosis epithelial cells with estradiol, medroxyprogesterone acetate, tumor necrosis factor-, and interferon- stimulated measurable eotaxin secretion into the conditioned media. The results indicate that eotaxin is produced in epithelial cells of normal endometrium and endometriosis tissues, varies across the menstrual cycle, and is elevated in women with endometriosis. We postulate that eotaxin, interacting with other known cytokines and immune cells, contributes to an inflammatory reproductive tract environment, leading to endometrial or blastocyst dysfunction.

	Introduction

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ENDOMETRIOSIS is a common, but complex, gynecological syndrome of unknown pathogenesis that affects 5–15% of reproductive-aged women. It commonly is accompanied by debilitating symptoms of dysmenorrhea, pelvic pain, and reduced fecundity. Although multiple theories of the histogenesis of endometriosis exist, the implantation hypothesis of Sampson (1) is the most widely accepted. Retrograde menstruation (2) and intraperitoneal spillage of viable endometrial cells (3) occur frequently in cycling women, and müllerian tract outflow obstruction is associated with an increased prevalence of endometriosis (4).

The pathophysiology of endometriosis-associated pain and infertility remains enigmatic, but current evidence suggests that these symptoms result from local inflammation at the implant sites (5). Pelvic implants are associated with gross and microscopic evidence of local inflammatory changes, viz. neovascularization, fibrous scarring, and accumulation of activated inflammatory cells (6). It has been proposed that the recruitment of pelvic immune cells initiates an intraperitoneal cascade of cytokines that mediate the pain and infertility that accompany endometriosis (7).

Autoinflammatory phenomena, including autoantibody production and atopy, have been associated with endometriosis. Mathur and her colleagues (8, 9) were the first to describe, in this disease, autoantibodies that recognize endometrial proteins ranging in size from 34–140 kDa. Similar results have been confirmed by other groups (10, 11). Gleicher and colleagues (12) noted that a significant proportion (40–60%) of women with endometriosis has elevated autoantibody titers when tested against a panel of common, generic autoantigens (e.g. phospholipid, ribonucleoprotein, and double-stranded DNA). Thus, in addition to the development of specific antiendometrial antibodies, generalized polyclonal B-cell activation is associated with some cases of endometriosis (13).

A highly significant correlation has been noted between surgically documented endometriosis and the incidence of atopic allergic symptoms (14). This association was confirmed in a recent survey, conducted by the Endometriosis Association, of 4,000 North American women (15). In that study, 41% and 17% of surveyed endometriosis patients reported a history of pollen allergy and eczema, respectively, compared with 13% and 6% of women in the general population. In a cohort of 40 endometriosis patients with a predominant complaint of fatigue, 65% had allergy symptoms and positive serum IgE and IgG radioallergosorbent tests (D. Metzger, personal communication). On the basis of these clinical findings, which suggest an autoinflammatory or allergic component in endometriosis, we hypothesized that the biochemical mediators of atopic reactivity might be increased in women with this syndrome. As a prototype for such molecules, we selected the 8.4-kDa C-C eosinophil chemokine, eotaxin, and first investigated its peritoneal fluid concentrations in a case-control study of subjects with endometriosis and matched, normal women. These findings were then extended, using an established endometriosis cell model (7), to determine whether eotaxin protein secretion could be induced in vitro via endocrine and/or paracrine effectors.

	Subjects and Methods

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Patient recruitment and characterization

Healthy ovulatory women, who had not received hormones or GnRH agonist therapy for at least 6 months before surgery, were recruited, after they had provided written informed consent, under a study protocol approved by the UCSF Committee on Human Research at the University of California, San Francisco. Women with endometriosis (n = 15) were staged intraoperatively, according to a modification of the revised American Fertility Society system, in which the extent of active endometriosis lesions were scored (5). Control subjects (n = 7) were women with subserosal leiomyomata or uterine descensus or requesting tubal ligation without evidence of pelvic pathology.

Sources of tissues and peritoneal fluid

Tissue specimens and peritoneal fluid samples were obtained from patients undergoing laparoscopy or laparotomy. Endometrial and endometriosis biopsies were collected under sterile conditions for cell culture and immunohistochemical analyses. All samples and cycle stages were estimated histologically according to the criteria of Noyes et al. (16). All normal endometrial biopsies were in phase and consistent with the patients’ menstrual dating.

Peritoneal fluid was aspirated immediately upon entering the peritoneal cavity, cells were removed by centrifugation, and aprotinin (15 nmol/L) was added to the supernatant before freezing at -70 C. Pelvic fluid, endometriosis specimens, and all biopsies for cell culture were taken in the midproliferative phase of the cycle, as described previously (7).

Immunohistochemistry

Endometrial and endometriosis tissues were either frozen or fixed for 24 h in 2% paraformaldehyde and 0.5% glutaraldehyde, paraffin-embedded, cut in serial sections of 5 µm, and stained using the Vectastain Elite ABC kit (Vector Laboratories, Inc. Burlingame, CA). Immunoperoxidase staining was performed overnight at 4 C using mouse monoclonal IgG antibodies against human cytokeratin 18 (1:2000 dilution, Sigma, München, Germany) and eotaxin (1:50 dilution, R&D Systems, Wiesbaden, Germany). Controls for the immunostaining specificity included sections stained with antieotaxin antibodies (1:50 dilution) immunoabsorbed with 1.2 µmol/L recombinant eotaxin protein (R&D Systems). Diaminobenzidine (Zymed Laboratories, Inc., South San Francisco, CA) was used as the chromagen. All sections also were lightly counterstained with hematoxylin. Eight blinded observers scored the immunostaining intensity, from 0 (no staining) to 4 (most intense staining), relative to a cytokeratin positive control. The mean ± SD score of the eight observers is reported.

Human endometrial and endometriosis cell cultures

Primary endometrial and endometriosis cell cultures were prepared from biopsies, as we have described previously (7). Glandular epithelial cells were separated from stromal cells and debris by filtration through narrow-gauge sieves. Stromal cells were subcultured to eliminate contamination by macrophages or other leukocytes, and experiments were performed at passage 2. Extensive characterization of cell cultures, prepared using this protocol, confirmed that they were more than 95% pure and retained functional markers of their endometrial and endometriosis origin in vivo (17). At the end of each experiment, cells were counted using the acid phosphatase colorimetric assay described by Ueda et al. (18).

Steroid and cytokine treatment of endometrial and endometriosis cell cultures

When the primary cell cultures approached confluence, the complete medium was removed and replaced with fresh -MEM containing 2.5% FCS and antibiotics, and the cells were cultured for an additional 48 h with tumor necrosis factor- (TNF-; 5.9 nmol/L, Sigma), interferon- (IFN-; 4.2 nmol/L, Sigma), 10 nmol/L estradiol (E₂, Merck & Co., Inc., Darmstadt, Germany), and/or 100 nmol/L medroxyprogesterone acetate (MPA, Sigma). MPA was used in place of natural progesterone because it is more slowly metabolized in tissue culture. This combination of cytokines and steroids showed maximal stimulatory effects in prior experiments (5, 7, 17) and was selected to model the secretory phase of the endometrial cycle in vitro.

Eotaxin enzyme-linked immunosorbent assay (ELISA)

Eotaxin concentrations were measured using a sandwich ELISA (R&D Systems). This assay uses murine monoclonal antibodies and goat polyclonal antibodies against eotaxin. The assay does not cross-react with several cytokines that are closely related to eotaxin, including MCP-1, MCP-2, MCP-3, MIP-1, MIP-1ß (macrophage inflammatory protein-1 and ß), and RANTES (regulated upon activation, normal T cell-expressed and secreted). The sensitivity limit of the assay was 0.6 pmol/L, with intraassay coefficients of variation less than 6% and interassay coefficients of variation less than 12%.

Statistical analysis

All experiments were repeated a minimum of three times, and the results are presented as the mean ± SD. Kolmogorov-Smirnov analyses demonstrated that the distribution of the results was Gaussian and did not differ between normal and endometriosis cases (P = 0.31). The data were analyzed by ANOVA with Fisher’s post hoc tests for multiple comparisons. Linear regression analysis was performed to determine the correlation between disease severity and pelvic fluid eotaxin concentration. Significant differences were accepted when two-tailed analyses yielded P < 0.05.

	Results

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Eotaxin immunolocalization in endometrial and endometriosis tissues

Immunohistochemistry was used to localize eotaxin protein in fixed and frozen tissue. A section of normal proliferative endometrium, stained with hematoxylin and eosin, is shown in Fig. 1A. In an adjacent section, monoclonal antibodies against cytokeratin specifically stained the glandular and luminal epithelium (Fig. 1B). Monoclonal mouse IgG antibodies against eotaxin showed this antigen to be localized primarily in the epithelium, with the stromal compartment appearing relatively free of the antigen (Fig. 1C). Control experiments were performed on serial sections of endometrium using eotaxin antibodies immunoabsorbed with excess eotaxin protein (Fig. 1D). Experiments with frozen sections revealed the same staining pattern (data not shown). During the secretory phase of the cycle, we observed increased amounts of eotaxin immunoreactivity, and the epithelial cells were more distinctively highlighted than in proliferative phase endometrium (Fig. 1E). The specificity of the staining pattern is shown again, after immunoabsorption with an excess of pure recombinant human eotaxin (Fig. 1F). Normal secretory endometrium demonstrated more luminal than glandular eotaxin staining (Fig. 1G). Endometriosis tissues also demonstrated eotaxin protein. A section of an ovarian endometrioma stained with eotaxin showed patterns very similar to those observed in normal endometrium (Fig. 1H).

View larger version (146K): [in this window] [in a new window]   Figure 1. Immunohistochemistry of eotaxin in human endometrial and endometriotic tissues. Paraffin-embedded sections of normal, proliferative-phase endometrium were stained with hematoxylin and eosin (A), anticytokeratin antibodies to label epithelial cells (B), and antieotaxin antibodies (C). The predominantly epithelial staining of eotaxin was obliterated when the latter antibodies were preabsorbed with excess eotaxin protein (D). Sections of secretory endometrium showed strong, epithelial eotaxin staining (E), which also was eliminated by preabsorption with the antigen (F). Several sections of secretory endometrium revealed that eotaxin staining intensity was greater in the luminal epithelium than in glandular epithelium (G). Note that the dark appearance of the deep glands at the right side of the figure is attributable to densely packed, hematoxylin-positive nuclei, rather than brown immunoperoxidase product. Endometriotic epithelial cells stained intensely for eotaxin (H). Magnification, x400.

Eotaxin concentrations in peritoneal fluid specimens

Peritoneal fluid from women with endometriosis and from women without the disease was collected and assayed for secreted eotaxin, by ELISA. All peritoneal fluids were obtained in the midproliferative phase of the cycle. There was a slight increase, but not statistically significant difference, between controls (11.0 ± 3.7 pmol/L) and patients with minimal or mild endometriosis (13.8 ± 6.3 pmol/L; modified American Fertility Society (AFS) stages I and II). But women with moderate-to-severe endometriosis, based on active implant scoring (see Ref. 24 ; modified AFS stages III and IV), had significantly higher concentrations of peritoneal fluid eotaxin (20.6 ± 6.5 pmol/L) than women without disease or those with minimal or mild disease (P < 0.05; Fig. 2). There was a positive correlation (r = 0.56) between the severity of endometriosis and the concentration of eotaxin in peritoneal fluid (P < 0.01).

View larger version (16K): [in this window] [in a new window]   Figure 2. Peritoneal fluid concentrations of eotaxin were determined using a sensitive ELISA. Pelvic fluid was collected during the midproliferative phase of the menstrual cycle. Subjects were classified as having no evidence of endometriosis (controls, n = 7), minimal-moderate endometriosis (modified AFS stages I-II, n = 8), or moderate-severe endometriosis (modified AFS stages III-IV, n = 7). The latter group had significantly higher peritoneal fluid eotaxin concentrations (ANOVA with Fisher’s post hoc tests; *, P < 0.05).

To determine whether isolated human endometrial cells preserved the capacity to secrete eotaxin, these were grown to confluence and treated for 48 h with E₂ (10 nmol/L), MPA (100 nmol/L), TNF- (5.9 nmol/L), and IFN- (4.2 nmol/L) or not stimulated. Conditioned media were collected after 48 h and assayed for secreted eotaxin, by ELISA. Neither normal endometrial nor endometriosis stromal cells secreted measurable eotaxin protein under any conditions (<1.2 fmol eotaxin/100,000 cells). Likewise, normal endometrial epithelial cells failed to secrete eotaxin under any of the above conditions. However, conditioned media from isolated endometriosis epithelial cells contained 856 ± 181 fmol eotaxin/100,000 cells after 48 h stimulation with E₂ (10 nmol/L), MPA (100 nmol/L), TNF- (5.9 nmol/L), and IFN- (4.2 nmol/L). Unstimulated endometriosis epithelial cells or those stimulated with either cytokines or steroids alone had no measurable eotaxin protein. Only the combination of these factors stimulated the endometriosis epithelial cells to secrete detectable eotaxin (ANOVA, P < 0.01).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Eotaxin was initially identified as a specific chemoattractant protein for eosinophils; however, recent studies indicate that it may dictate a broader scope of activities on myeloid cells during development and in pathological states (19). The detection of immunoreactive eotaxin protein in normal endometrium (Fig. 1; C, E, and G) and more intense staining in endometriosis biopsies (Fig. 1H) indicates that these tissues have the potential to accumulate this chemokine. A caveat is that the latter observation is cross-sectional, because the same women did not have simultaneous eutopic and ectopic biopsies compared. The distribution of eotaxin staining essentially was confined to the epithelial layer, similar to observations made in guinea pig lung (20). Whereas this pattern is the same as that reported for the related C-C monocyte chemokine MCP-1 (21), it is quite distinct from our localization of the C-C monocyte chemokine RANTES in the stromal compartment of normal endometrium and endometriosis implants (7). These findings indicate that the accumulation of immune cell activator proteins in human endometrium and endometriosis is remarkably cell specific. As reported for MCP-1 (22) and RANTES (7), normal endometrial eotaxin accumulation seems to be regulated during the menstrual cycle, with enhanced protein in the secretory phase (Fig. 1G).

Our recent detection of eotaxin mRNA transcripts in endometriosis implants, by reverse transcription-PCR (data not shown), and the de novo synthesis of eotaxin by isolated endometriosis epithelial cells suggest that the eotaxin gene is expressed in this tissue. Stromal cells isolated from normal endometrium and endometriosis lesions failed to secrete eotaxin under basal, cytokine, and/or steroid hormone-stimulated conditions (<1.2 fmol/100,000 cells). Epithelial cells isolated from normal endometrium likewise did not secrete immunodetectable eotaxin under basal, cytokine, and/or steroid hormone-stimulated conditions (<1.2 fmol/100,000 cells). However, epithelial cells derived from endometriomas were induced to secrete 856 ± 181 fmol eotaxin/100,000 cells after treatment with cytokines and steroid hormones (P < 0.01).

Pelvic fluid concentrations of eotaxin were correlated positively with endometriosis stage (r = 0.56, P < 0.01) and were statistically elevated in women with advanced stages (AFS stages III and IV) of active disease. This observation is similar to previous studies of TNF- (23), interleukin-8 (24), and vascular endothelial growth factor (25) and supports the proposal that active endometriosis lesions secrete eotaxin and other cytokines into the peritoneal environment. Our results indicate that endometriosis epithelial cells have a preferential ability to synthesize and secrete eotaxin, relative to those derived from normal endometrium. Production of this eosinophil chemokine seems to be under both endocrine and paracrine control, with enhanced secretion under conditions that mimic the secretory phase of the menstrual cycle. The precise role of eotaxin in the pathogenesis of endometriosis remains to be elucidated; however, our findings suggest that autoinflammatory and allergic phenomena associated with this syndrome may be linked to the recruitment of eosinophils and other myeloid cells into the peritoneal cavity. This hypothesis is currently under investigation in our laboratories.

	Footnotes

 
¹ These studies were supported by Fortune-Project F1241133 and a grant from the NIH/NICHD, through cooperative agreement U54-HD-37321, as part of the Specialized Cooperative Centers Program in Reproduction Research.

Received November 29, 1999.

Revised March 4, 2000.

Accepted March 22, 2000.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hornung, D. Articles by Taylor, R. N. Search for Related Content PubMed PubMed Citation Articles by Hornung, D. Articles by Taylor, R. N.