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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 3 1397-1401
Copyright © 2004 by The Endocrine Society

Peritoneal Macrophages Induce RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted) Chemokine Gene Transcription in Endometrial Stromal Cells

Dan I. Lebovic, Victor A. Chao and Robert N. Taylor

Reproductive Endocrinology Division, Department of Obstetrics and Gynecology, University of Michigan (D.I.L.), Ann Arbor, Michigan 48109-0276; and Center for Reproductive Sciences, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California (V.A.C., R.N.T.), San Francisco, California 94143-0556

Address all correspondence and requests for reprints to: Dr. Dan I. Lebovic, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan 48109-0276. E-mail: lebovic{at}umich.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Peritoneal fluid macrophages (PFM) are activated in women with endometriosis, in whom they are thought to mediate or exacerbate inflammation. The effect of PFM on endometrial stromal cells (ESC) was studied using a coculture model to evaluate the influence of IL-1ß and other macrophage-derived cytokines on the transcriptional activation of the human RANTES (regulated on activation, normal T cell expressed and secreted) gene. Normal endometrial biopsies from four patients were used to prepare stromal cell cultures, and pelvic fluid was collected to isolate peritoneal macrophages. A full length (-940 bp) human RANTES promoter construct provided an indicator of transcriptional activation in luciferase reporter transfection assays. Without lipopolysaccharide (LPS), cocultures with PFM had no effect on ESC RANTES gene expression. However, when PFM were treated with LPS within the coculture apparati, ESC RANTES promoter activity was increased more than 2-fold (P < 0.05). The addition of IL-1 receptor antagonist abrogated activation of the RANTES luciferase transgene by LPS-induced PFM products (P < 0.05). We identified IL-1 from PFM as a major stimulus to initiate ESC RANTES gene expression in cocultures. We postulate that PFM stimulation of RANTES production by ESC could lead to a self-propagating recruitment of inflammatory cells that contribute to the development and progression of endometriotic lesions.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
RETROGRADE MENSTRUATION, FIRST proposed by Sampson (1) in 1927 as the etiology of endometriosis, appears to be ubiquitous among ovulatory women (1A ). However, menstrual debris that persists in the pelvis may do so as a result of a defective innate immune response, and the latter may predispose the 10–15% of women who develop this disorder. It has been suggested that ectopic endometrial tissue can stimulate an incomplete inflammatory reaction that fails to eliminate these displaced cells (2). The accumulation of activated macrophages in endometriotic lesions (3) and peritoneal fluid of women with endometriosis appears to initiate or sustain the disease by secreting mitogenic factors (4, 5) and angiogenic proteins (6) from endometrial stromal cells. This chronic, inflammatory response is exacerbated further by the decreased cytotoxicity of lymphocytes and natural killer cells toward endometrial cells in this condition (7, 8, 9).

The inflammatory milieu in the peritoneal cavity of women with endometriosis has been extensively characterized. Peritoneal fluid specimens from women with endometriosis have elevated levels of a variety of cytokines, including IL-1ß, TNF{alpha}, IL-6, IL-8, and RANTES (regulated on activation, normal T cell expressed and secreted), compared with normal controls (10).

RANTES is an 8-kDa secreted protein with chemoattractant actions on monocytes, natural killer cells, T cells, and eosinophils (11, 12). We reported that concentrations of RANTES are elevated in the peritoneal cavity of women with endometriosis and correlate with the severity of the disease (13). We and others have shown that a predominant activated macrophage product, IL-1ß, induces RANTES gene expression in endometrial stromal cells (14, 15).

It has been proposed that soluble secreted factors from activated peritoneal fluid macrophages (PFM) play a role in the pathogenesis of endometriosis and its sequelae. Our prior research indicated that RANTES is a critical chemoattractant in the inflammatory cascade associated with endometriosis, and that regulation of this chemokine occurred at the level of gene transcription (14). The objective of the current study was to test the hypothesis that soluble factors released by PFM could induce transcription of the RANTES gene in endometrial stromal cells (ESC). To answer this question, we developed a coculture model using ESC that were transiently transfected with RANTES promoter-luciferase constructs and incubated with PFM. The model afforded a sensitive assay to evaluate PFM-derived mediators of RANTES gene transcription.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Sources of tissues

Tissue specimens were obtained from patients undergoing laparoscopy for tubal ligation sterilization after providing written informed consent under a study protocol approved by the institutional review board at University of California (San Francisco, CA). Healthy ovulatory women, who had not received hormonal therapy for at least 6 months before surgery, were recruited. None of the patients volunteering for this study had a history of endometriosis or showed any suspicious lesions for endometriosis at the time of surgery. Endometrial biopsies were collected under sterile conditions and transported to the laboratory on ice in MEM{alpha} with 10% fetal bovine serum (FBS). All endometrial biopsies were performed in the midproliferative cycle phase, and the histology was consistent with the patient’s menstrual dating. The tissues were collected in the midproliferative phase of the menstrual cycle to minimize the effects from luteal phase steroids. Our laboratory has shown that progestin treatment can suppress RANTES production in ESC (16).

Human endometrial cell cultures

Endometrial cell cultures were prepared from endometrial biopsies, as we have described previously (17). Glandular epithelial cells were separated from stromal cells and debris by filtration through narrow gauge sieves. ESC were subcultured at least twice to eliminate contamination by macrophages or other leukocytes. ESC cultures were used before the sixth passage for these experiments. Prior studies in our laboratory characterized ESC cultures prepared using this protocol and confirmed that they were more than 95% pure and retained functional markers of their endometrial origin in vitro (17). Moreover, these cells retain their ability to express vimentin, RANTES, and prolactin proteins for at least five passages.

Collection of peritoneal fluid and isolation of macrophages

PFM also were collected in the midproliferative phase of the ovulatory cycle of normal controls. Peritoneal fluid was collected in a sterile manner at the time of laparoscopic tubal ligation (no evidence of endometriosis was noted at surgery), immediately after insertion of the first supplemental trocar. Bloody samples, potentially contaminated with peripheral leukocytes, were excluded from our studies. Cells were collected by centrifugation at 2000 x g, and the pellet was resuspended in RPMI 1640 medium (Life Technologies, Inc., Grand Island, NY). The suspension was laid over 60% Percoll (Pharmacia Biotech, Uppsala, Sweden) and centrifuged at 2000 x g for 15 min. PFM were then collected from the medium-Percoll interface, resuspended with RPMI 1640 medium in 10-cm petri dishes, and allowed to grow to confluence. PFM were identified by CD36 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) immunocytochemical staining using 10 µg/ml rabbit antihuman CD36. An identical concentration of nonimmune rabbit antiserum was used as a negative control. PFM were passaged twice to minimize cell activation and to make the preparations more uniform.

Confluent PFM cultures were trypsinized and resuspended in MEM{alpha} supplemented with 10% FBS, and 30,000 cells were aliquoted into the upper chamber of 0.4-µm pore size, 24-well Transwell cell culture inserts (Falcon, BD Biosciences, Franklin Lakes, NJ) in 0.5 ml MEM{alpha}. The PFM-containing coculture inserts were introduced into the wells containing approximately 30,000 transfected ESC. Before addition of the stimuli, the medium was changed to a low serum medium (MEM{alpha} supplemented with 2.5% FBS, antibiotics, nucleosides, and nonessential amino acids) for 24 h. Dose-response pilot studies were performed to determine the optimal concentrations of stimuli. 1) Lipopolysaccharide (LPS) at 0.4 µg/ml (40 nM) significantly increased IL-1ß protein production compared with vehicle control (438 vs. 3.9 pg/ml/100,000 peritoneal fluid macrophages). 2) IL-1ß at 10 ng/ml (0.6 nM) maximally activated ESC RANTES production (14). 3) IL-1 receptor antagonist (IL-1ra; 250 ng/ml; 15 nM) was preincubated for 2 h in replicate wells of ESC, and IL-1ß was then added for 18–24 h. This IL-1ra concentration inhibited the 0.6 nM IL-1ß stimulatory effect on RANTES promoter activation. The same concentration of IL-1ra was selected for the PFM coculture experiments. To confirm that the culture medium did not confound the protein analyses, the 2.5% FBS-supplemented MEM{alpha} used for these experiments was tested for IL-1ß and RANTES concentrations, and both cytokines were below the limits of ELISA detection (<8 pg/ml).

Reporter genes and expression vectors

The full-length (940-bp) human RANTES promoter (18) was subcloned into the pGL2 vector (Promega Corp., Madison, WI). The construct was sequenced by the University of California-San Francisco Biomolecular Resource Center to verify that this was correct.

Transient ESC transfections

Subconfluent ESC were collected by centrifugation, and the pellet was resuspended in Dulbecco’s PBS (1.5 x 107 cells/0.5 ml) containing 0.1% glucose, 10 µg/ml Biobrene (Fisher Scientific, Pittsburgh, PA), and respective reporter plasmids. Three micrograms of pGL2-RANTES promoter (firefly luciferase, experimental reporter) and the suspended cells were transferred to a cuvette and kept at room temperature for 5 min. The cells were electroporated using a gene pulser (Bio-Rad Laboratories, Hercules, CA) set at 300 V and 975 µF. The electroporated cells were then transferred to 6.5 ml MEM{alpha} with 10% FBS and antibiotics. Using this method the transfection efficiency obtained with ß-galactosidase reporter vectors in ESC was 40%. The cells were recovered in medium for 5 min and then resuspended, and 100,000 ESC were plated at 0.5 ml/dish in 24-well multiplates and allowed to proliferate to 80% confluence.

Luciferase reporter assays

ESC extracts for luciferase assays were prepared with reporter lysis buffer (Promega Corp.), and luciferase activity was measured using a TD 20/20 luminometer (Turner Designs, Sunnyvale, CA) with a commercial dual luciferase kit from Promega Corp. The luciferase transfection efficiencies were normalized to an independent control plasmid (2.0 µg Renilla luciferase reporter) and are reported as relative light units. Positive and negative controls for the luciferase assays were provided by cytomegalovirus-luciferase and cytomegalovirus-ß-galactosidase plasmids, respectively.

Statistical analysis

In addition to being replicated in four independent ESC isolates, each assay was performed in quadruplicate. The data were analyzed by ANOVA with a post hoc Tukey test or paired t tests as appropriate. Results are presented as the mean ± SEM. Significant differences were accepted when two-tailed analyses yielded P < 0.05 (19). NS indicates no significant difference from control conditions.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
PFM and ESC cultures

The isolated pelvic fluid cells from the study subjects were stained with rabbit antihuman CD36 antiserum (data not shown). Several slides from different experiments after two passages of adherent cells showed 80–90% of the cells labeled with the antibody, indicating that they were characteristic of PFM. CD36 is a macrophage scavenger receptor that binds thrombospondin and oxidized low density lipoprotein, but does not distinguish between activated and nonactivated PFM (20, 21). Nonimmune rabbit serum, used as a negative control, showed only faint background staining (data not shown). ESC isolated under the described conditions have been characterized extensively in previous studies and represent a phenotype typical of their endometrial tissue of origin (17).

Effect of LPS-treated macrophages on transcriptional activation of the RANTES gene promoter in transfected ESC

To assess the ability of cytokines and PFM-secreted factors to activate RANTES gene transcription in transfected ESC, isolated cultures of the latter and cocultures of the two cell types were established using Transwell chambers. LPS had no direct effect on the RANTES-luciferase construct in transfected ESC alone, whereas IL-1ß-treated ESC led to a 4.5-fold increase in transgene activation (Fig. 1Go; P < 0.05). Failure of LPS to stimulate ESC cytokine production has been noted previously (17).



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  		FIG. 1. Transcriptional activation quantified using the full-length RANTES promoter-reporter construct. Luciferase reporter gene assays of transiently transfected ESC were performed using the full-length RANTES promoter (-940 bp). Transfection efficiency was normalized by Renilla luciferase. In isolated ESC, LPS had no direct effect while IL-1ß treatment led to a 4.5-fold increase in transgene activation (*, P < 0.05, by ANOVA, post hoc Tukey test). Error bars show SEs among four different ESC isolates. RLU, Relative light units.

 
In the absence of LPS, cocultures with PFM had no effect on ESC RANTES gene expression (Fig. 2Go; P = NS). However, when LPS was added to the PFM medium within the coculture apparati, ESC RANTES gene promoter activity was increased more than 2-fold (Fig. 2Go; P < 0.05). These results indicate that the observed effect within the coculture model is not a direct consequence of LPS treatment on ESC, but is an effect mediated by the PFM.



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  		FIG. 2. Transfection results with full-length RANTES promoter-reporter construct in the coculture model. Luciferase reporter gene assays were performed in ESC cocultured with PFM using the full-length RANTES promoter (-940 bp). Transfection efficiency was normalized by Renilla luciferase. ESC cultured without PFM showed no significant difference in RANTES gene expression with or without added LPS. Cocultures with untreated PFM had no effect on ESC RANTES gene expression (P = NS), whereas when LPS was added to the PFM medium, ESC RANTES gene promoter activity was increased more than 2-fold (*, P < 0.05, by ANOVA, post hoc Tukey test). Error bars show SEs among four different ESC isolates. RLU, Relative light units.

 
Effect of IL-1ra on the macrophage-ESC coculture model

IL-1ra was added to the coculture model to test the hypothesis that IL-1 is a major RANTES transcription-promoting cytokine product from LPS-treated PFM. As before, RANTES promoter-reporter constructs were transiently transfected into ESC with macrophages placed into overlying cell culture inserts treated with LPS in the presence or absence of recombinant IL-1ra. Addition of this natural antagonist of IL-1 abrogated the LPS-induced activation of the RANTES-luciferase transgene in the coculture model (Fig. 3Go; P < 0.05).



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  		FIG. 3. Transfection results using IL-1ra and the full-length RANTES promoter-reporter construct in the coculture model. Luciferase reporter gene assays in ESC cocultured with PFM were performed using the full-length RANTES promoter (-940 bp). Transfection efficiency was normalized by Renilla luciferase. Addition of IL-1ra abrogated the LPS-induced activation of the RANTES gene promoter in the coculture model (50% reduction in promoter activity; *, P < 0.05, by ANOVA, post hoc Tukey test). Error bars show SEs among four different ESC isolates.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Current concepts of the pathogenesis of endometriosis have elevated the immune system to center stage (2). Although estrogen clearly plays a decisive role in the sustenance of this disease, inflammatory proteins are thought to serve as the mediators of angiogenesis (6), endometrial lesion growth (22, 23), adhesion formation (15), and pain (24). Women with endometriosis have increased numbers of activated PFM (25, 26, 27) along with higher pelvic fluid concentrations of macrophage-derived cytokines (28, 29, 30, 31, 32, 33). The objective of the current study was to evaluate the influence of activated PFM on the induction of RANTES gene transcription in ESC using an in vitro coculture model system. The pleiotropic cytokine IL-1ß is a dominant cytokine secreted by activated macrophages (34) and is present at higher concentrations in peritoneal fluid of patients with endometriosis compared with those without endometriosis (29, 35, 36). IL-1 is a potent in vitro inducer of angiogenic proteins such as vascular endothelial growth factor and IL-6 in other cell types (37, 38, 39, 40) as well as in ESC. Northern blot analyses showed a particularly robust induction of vascular endothelial growth factor mRNA and IL-6 mRNA transcripts after IL-1ß treatment in stromal cells derived from endometriotic lesions (6).

Proliferative effects mediated by macrophages, as have been associated with idiopathic pulmonary fibrosis (41), also may be operative in endometriosis (22, 42). Surrey and Halme (43) found greater ESC proliferation when these cells were exposed to peritoneal fluid isolated from women with endometriosis compared with control fluid. Using an in vitro coculture model, Loh et al. (22) showed that human PFM isolated from women with endometriosis increased ESC proliferation compared with cocultures using normal PFM. It seems plausible that soluble factors produced from activated PFM lead to ESC proliferation. In fact, we found that IL-1ß down-regulated a cell regulatory gene responsible for inhibition of mitotic activity, transducer of ErbB, in ESC (23). IL-1ß thus provides an immunological link between PFM and the promotion of endometriotic implant growth and angiogenesis.

Endometriosis-induced pain is likely to be secondary to the release of inflammatory mediators or caused by chronic changes such as scarring, retraction, fibrosis, and adhesions. PFM from women with endometriosis release more prostaglandins (24), and a direct relationship between the severity of dysmenorrhea and prostaglandin production by endometriotic tissue was reported (44). Tamura et al. (45) found that IL-1ß significantly increased cyclooxygenase-2 and prostaglandin E2 concentrations in ESC. IGF-I is also a potent mitogen for fibroblasts (46, 47) and induces collagen synthesis in vitro (48). Estradiol augments the endometrial expression of IGF-I (49) and RANTES (15), and IL-1ß has been shown to increase IGF-I production in ESC (48).

RANTES concentrations in peritoneal fluid correlate positively with the clinical stage of endometriosis (13). ESC and other cell types express RANTES in response to IL-1ß (14, 50, 51, 52, 53). RANTES is involved in monocyte chemoattraction to regions of ongoing inflammation and injury (13, 54). The majority of monocyte chemotactic activity in peritoneal fluid from women with endometriosis appears to be mediated by RANTES (55). The RANTES gene promoter in ESC was found to contain a nuclear factor-{kappa}B response element that was critical for IL-1ß activation and up-regulation of RANTES gene transcription (14). However, to date there is no evidence that an activating RANTES promoter polymorphism is associated with endometriosis (56).

Our current studies tested the hypothesis that IL-1, released from stimulated PFM, can lead to further macrophage recruitment via RANTES gene expression in ESC through a feedforward regulatory loop. Coculture with LPS-treated PFM stimulated transcription of the RANTES promoter more than 2-fold. Previously we showed that a doubling of RANTES transcriptional activity corresponded to a 5-fold increase in steady state RANTES mRNA levels and a more than 10-fold increase in RANTES protein secretion (14). Using IL-1ra, an endogenous inhibitor that blocks the binding of IL-1 to IL-1 receptor type I, we identified IL-1 as an important functional PFM-derived cytokine responsible for RANTES gene promoter activity in our coculture model.

The results in the present study provide direct evidence that macrophage-induced soluble factors influence ESC production of RANTES chemokine. Our earlier work indicated that an IL-1ß effect on ESC was mediated by the IL-1 receptor type I via transcriptional activation of a proximal nuclear factor-{kappa}B element in the RANTES gene promoter (6, 14). Taken together, the findings suggest that the predominant inflammatory cells found in endometriotic lesions, activated macrophages, elaborate IL-1ß, which acts on ESC to facilitate the vascular establishment (angiogenesis), progression (growth), and inflammatory sequelae (pain and adhesions) of endometriotic tissues. Small molecules that target IL-1 production or action would thus be excellent candidates to mitigate the untoward symptoms of endometriosis.


   Acknowledgments
 
We thank the clinical staff of the Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California-San Francisco, for their generous contributions to the study. We also thank Evelyn Garrett (University of California, San Francisco, CA) for her assistance with the immunocytochemistry.


   Footnotes
 
This work was supported by the following NIH grants and fellowships: HD-08517 (to D.I.L.) and HD-37321 (to D.I.L. and R.N.T.), through the Specialized Cooperative Centers Program in Reproductive Research.

Abbreviations: ESC, Endometriotic stromal cells; FBS, fetal bovine serum; IL-1ra, IL-1 receptor antagonist; LPS, lipopolysaccharide; PFM, peritoneal fluid macrophages; RANTES, regulated on activation, normal T cell expressed and secreted.

Received June 11, 2003.

Accepted November 23, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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