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Biology of Reproduction 66, 401-406 (2002)
© 2002 Society for the Study of Reproduction, Inc.

Regular Article

Abnormal Interleukin-1 Receptor Type II Gene Expression in the Endometrium of Women with Endometriosis1

A. Kharfia, A. Bouchera, and A. Akoum2,a

a Unité d'Endocrinologie de la Reproduction, Centre de Recherche, Hôpital Saint-François d'Assise, Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Québec, Canada G1L 3L5


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Interleukin 1 (IL-1) is a major proinflammatory cytokine that is believed to play a central role in the pathophysiology of endometriosis. The IL-1 receptor type II (IL-1RII) is known to bind to IL-1 and to inhibit its biological effects. In our previous studies, we showed that human endometrium expresses IL-1RII, and we observed reduced expression of the protein in women with endometriosis. The aim of this study was to investigate IL-1RII mRNA in the endometrial tissue of normal women (n = 26) and of patients with various degrees of endometriosis (n = 53). In situ hybridization showed that IL-1RII mRNA expression was significantly decreased in endometriosis, particularly during the early stages of the disease (stages I and II). This was quite obvious in both glandular and stromal cells, and it was corroborated by reverse transcription-polymerase chain reaction analysis of IL-1RII mRNA in the endometrial tissue of women with (n = 10) and without (n = 8) endometriosis. The reduced levels of IL-1RII mRNA in the endometrium of women suffering from endometriosis reveals a profound defect in IL-1RII gene expression and, consequently, a reduced capability of endometrial tissue to down-regulate IL-1 activity. Defective IL-1RII gene expression during the early stages of endometriosis (stages I and II) may contribute to the etiology of the disease.

cytokines, female reproductive tract


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recent evidence has demonstrated a direct relationship between the immune and the reproductive systems [1]. Cytokines produced by leukocytes and various other cell types have a wide range of biological activities, including the ability to regulate immunological, neuroendocrine, and reproductive functions [2]. Among these cytokines, the interleukin 1 (IL-1) system appears to be relevant to various reproductive processes and to a broad spectrum of pathophysiological responses associated with host defense and inflammation [3, 4].

A cytokine having potent and inflammatory properties, IL-1 was shown to be involved in numerous immunological and reproductive activities occurring normally in the human endometrium during a normal menstrual cycle or during embryonic implantation and development [5]. A growing body of evidence indicates that IL-1 may play an important role in the pathophysiology of endometriosis, a gynecological disease that is believed to arise from ectopic growth of endometrial tissue and is associated with a chronic immunoinflammatory process [6–8]. In women with endometriosis, peripheral blood monocytes [9] as well as peritoneal macrophages [10] were found to be more activated than in normal women and to secrete elevated levels of IL-1. Increased concentrations of IL-1 were detected in the peritoneal fluid of women suffering from endometriosis [10, 11]. According to our previous data, IL-1 enhances the production of monocyte chemotactic protein-1 (MCP-1) by human endometriotic cells [12] and by eutopic endometrial cells of women with endometriosis [13]. Moreover, these cells appeared to be more sensitive to the action of IL-1 in women with than in women without endometriosis [14].

The effects of IL-1 likely are stringently controlled in vivo. A number of IL-1 inhibitors that can block the activity of IL-1 on target cells have been identified and partially characterized [15].

Three receptors for IL-1, now designated as IL-1RI, IL-1RII, and IL-1RIII (more commonly called IL-1R AcP [accessory protein]), have been described. The relative importance of these receptors in IL-1 signaling has been recently clarified. A critical role for the IL-1RI and IL-1R AcP in IL-1-induced cell activation has been demonstrated by several groups [16–18]. In contrast, IL-1RII appears to be dispensable for IL-1 signaling and may act as a decoy receptor [16, 17]. Interleukin-1 receptor antagonist (IL-1ra) is another natural inhibitor of IL-1, which competes with IL-1{alpha} and IL-1ß for IL-1 RI [19]. Results of several studies indicate that the IL-1 system is available locally in the human endometrial tissue and may be an important mediator in local cellular interactions [20–24]. However, few studies have focused on the possible role of this system in the pathophysiology of endometriosis. According to Sahakian et al. [8], ectopic endometrial tissue does not express IL-1ra. According to our previous studies, the endometrial tissue of women with endometriosis expresses low levels of IL-1RII protein compared with that of healthy women [25]. The aim of this study was to investigate the expression of IL-1RII at the level of mRNA in the endometrium of women with and of women without endometriosis. Alteration of the IL-1RII gene expression may provide molecular evidence for a deficient control of IL-1 in the eutopic endometrial tissue of women with endometriosis.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and Tissue Collection

Endometrial tissues were obtained from 79 women aged between 30 and 36 yr who were undergoing laparoscopic surgery for infertility, pelvic pain, or tubal ligation and who had not received any anti-inflammatory or hormonal medication during a period of at least 3 mo before laparoscopy. Fifty-three women had endometriosis of various stages (I, II, III, and IV) according to the revised American Fertility Society classification [26]. Twenty-six women were fertile and had no visible endometriosis at laparoscopy (Table 1). The cycle phase was determined according to the cycle history, progesterone levels in the serum, and histologic criteria. An informed consent was obtained from each patient, and the study was approved by the ethical committee of the "Centre Hospitalier Universitaire de Québec" (CHUQ).


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  		TABLE 1. Clinical characteristics of patients at laparoscopy

Endometrial samples were collected with a curette before laparoscopy. The tissue was placed in cold, sterile Hanks buffered saline containing antibiotics, then immediately transported to the laboratory and snap-frozen in liquid nitrogen before being stored at -80°C.

Fluorescence In Situ Hybridization

The present experiments were performed as previously described [13]. Briefly, biotin-labeled IL-1RII cDNA probe was prepared by nick translation [27] from the entire plasmid vector pcDNA3 (a gift from P. Bossü, Dompé SpA, L'Aquila, Italy).

Cryosections (thickness, 5 µm) from 79 endometrial tissues (Table 1) were fixed with formaldehyde and dehydrated with alcohol before being hybridized with 5 ng/ml of biotinylated IL-1RII cDNA probe. Biotin was then detected using a rabbit antibiotin antibody, a biotinylated goat anti-rabbit antibody, and fluorescein isothiocyanate-conjugated streptavidin, respectively. Sections were finally treated with propidium iodine, which makes the nucleus visible in yellow-orange following ultraviolet excitation, and were observed under a fluorescence microscope (Leica mikroskopie und systeme GmbH, Model DMRB, Postfach, Wetzlar, Germany). Serial sections from each tissue incubated without IL-1RII cDNA probe or with nonspecific DNA probes prepared from the plasmid vector alone were used as negative controls.

Evaluation of Staining

Staining was evaluated using an arbitrary scale as previously reported [13]. In brief, each endometrial section was graded according to the intensity of staining three times in three different, randomly selected areas and scored from 0 to 3 (0 = absent, 1 = light, 2 = moderate, and 3 = intense). Grading of each specimen was performed by two different observers who had no knowledge of the clinical status of the patients including laparoscopic diagnosis.

Reverse Transcription-Polymerase Chain Reaction

Total RNA from the endometrial tissue of 8 normal women (3 in the proliferative phase and 5 in the secretory phase) and of 10 women with stage I–II endometriosis (4 in the proliferative phase and 6 in the secretory phase) was extracted using a Trizol reagent according to the manufacturer's instructions (Gibco BRL, Burlington, ON, Canada). Total RNA (500 ng) was reverse transcribed into cDNA using 50 U of reverse transcriptase in the presence of random hexamer primers (2.5 µM), dNTPs (1 mM each), 1 U/µl of RNase inhibitor, 10 mM Tris-HCl, 50 mM KCl, and 5 mM MgCl2 (Gene Amp PCR Core Kit; Perkin-Elmer, Foster City, CA). The reaction was incubated at 25°C for 15 min, 42°C for 30 min, and 99°C for 5 min. Two microliters of the reverse transcription (RT) reaction were used for polymerase chain reaction (PCR) in a final volume of 50 µl with 100 pmol of each IL-1RII primer (5': TCC ATG TGC AAA TCC TCT CTT; 3': TCC TGC CGT TCA TCT CAT ACC; expected amplimer length, 576 bp), 0.2 mM dNTPs, 2 mM MgCl2, and 2.5 U of Taq polymerase [28]. Amplification was performed for 30 cycles consisting of 1 min of denaturation (94°C), 30 sec of annealing (60°C), and 1 min of primer extension (72°C). Glyceraldehyde phosphate dehydrogenase (GAPDH) was used as a control. Four microliters of the RT reaction were used for PCR in a final volume of 50 µl with 25 pmol of each primer (5': TGA TGA CAT CAA GAA GGT GGT GAA G; 3': TCC TTG GAG GCC ATG TGG GCC AT; amplimer size 240 bp), 0.2 mM dNTPs, and 1 U of Vent DNA Polymerase (New England Biolabs, Beverly, MA). Amplification was performed for 30 cycles consisting of 30 sec of denaturation (95°C), 30 sec of annealing (60°C), and 1 min of primer extension (72°C). These optimal conditions were determined following linearity tests using 1, 2, 4, and 8 µl of the RT reaction volume and 25, 30, and 35 amplification cycles. Amplification of genomic DNA with these primers did not produce a signal, suggesting that the amplification sites crossed at least one intron/exon boundary. A total of 20% of the PCR volume was then analyzed on a 1% (w/v) agarose gel in the presence of ethidium bromide and transferred to Qiabrane Nylon Plus membranes (Qiagen, Santa Clarita, CA). Membranes were dehydrated at 37°C for 30 min, prehybridized with a hybridization buffer, hybridized in the same buffer (without Denhardt solution) with 32P-labeled IL-1RII or GAPDH cDNA, and washed in 1x 0.15 M sodium chloride and 0.015 M sodium citrate (SSC), 0.2x SSC, and 0.1% SDS, respectively, before being exposed to x-ray film (Eastman Kodak, Rochester, NY).

Specificity of the amplification process was verified by Southern blot hybridization. A negative control (PCR in the absence of cDNA) as well as a positive control (cDNA preparation from human endometrial tissue expressing IL-1RII) were included in each series of IL-1RII or GAPDH amplification. The quantity of the PCR products was determined by densitometric analysis of the intensity of the hybridization signal. The relative level of IL-1RII mRNA normalized to GAPDH mRNA was calculated, and the results were expressed as a % of the control value (positive control).

Statistical Analyses

The intensity of IL-1RII mRNA hybridization signals was expressed as arbitrary units. Statistical analysis was performed by the Fisher exact probability test [29], and Bonferroni correction was applied when more than two groups were compared. Analysis of IL-RII mRNA levels as determined by semiquantitative RT-PCR was performed using one-way ANOVA and the Tukey test for post-hoc multiple comparisons. All analyses were carried out using the Statistical Analysis System (SAS Institute, Inc., Cary, NC). Differences were considered to be statistically significant at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Analysis of IL-1RII Gene Expression in the Endometrium by In Situ Hybridization

The expression of IL-1RII mRNA in the endometrium was studied by in situ hybridization to examine the site of IL-1RII synthesis and to compare the levels of IL-1RII mRNA in patients with and without endometriosis. Figure 1 shows the appearance of endometrial stroma and glands at 666x magnification (A1 and B1) following hybridization and staining with propidium iodine. The hybridization signal (green-yellow) could only be visualized at higher magnification (1665x) and appeared to be located mainly in the endometrial glands (A2 and B2).



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  		FIG. 1. Illustration of IL-1RII mRNA expression in situ in the endometrium of normal women (A) and women with endometriosis (B). Sections were hybridized with biotin-labeled cDNA probes. Biotin detection was performed using a rabbit polyclonal antibiotin antibody, a biotinylated goat anti-rabbit polyclonal antibody, and fluorescein isothiocyanate-conjugated streptavidin, respectively. Propidium iodine was used to make the nucleus visible in yellow-orange on ultraviolet excitation. Note the appearance of endometrial glands (g) and stroma (s) at x666 magnification (A1 and B1). The hybridization signals (green-yellow; arrow) were visible at 1665x magnification (A2 and B2). Note the greater number of hybridization signals in a part of an endometrial gland from a normal woman (Day 13; A2) compared to that from a woman with stage I endometriosis (Day 14; B2)

As described earlier, an arbitrary score was used to quantify the IL-1RII mRNA hybridization signal. Statistical analysis of hybridization scores using the Fisher exact test showed a significant decrease in women with endometriosis compared to normal women, both in endometrial glands (P = 0.0001) and stroma (P = 0.006) (Table 2). Furthermore, when patients with endometriosis were grouped according to the stage of disease, a significant decrease in IL-1RII mRNA expression in the glandular (P = 0.0003) as well as the stromal (P = 0.012) compartment was observed in stage I. In stage II, a significant decrease in IL-1RII mRNA levels was also observed, but only in the glands (P = 0.042), whereas in more advanced stages (III and IV), no statistically significant difference was found. A graphical illustration of IL-1RII mRNA scores in normal controls and in women at different stages of endometriosis is shown in Figure 2.


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  		TABLE 2. Number of subjects according to intensity of the IL-1RII mRNA hybridization signal in the endometrium



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  		FIG. 2. Graphical illustration of IL-1RII mRNA hybridization scores in the endometrium of normal controls (n = 26) and of women with endometriosis of different stages (n = 53). A) Hybridization scores (mean ± SEM) in the glands. B) Hybridization scores (mean ± SEM) in the stromal compartment. *P < 0.05, **P < 0.01

The effect of the menstrual cycle on levels of IL-1RII mRNA in the endometrium was also evaluated. Statistical analysis of the hybridization scores showed no significant difference between the proliferative and the secretory phases within the control or the endometriosis groups. However, the decreased expression of IL-1RII mRNA observed in women with endometriosis was more noticeable during the secretory phase of the menstrual cycle, either in the glands (P = 0.003) or in the stroma, in which a statistically significant difference between women with and women without endometriosis was seen only during the secretory phase (P = 0.018) (Table 2).

Statistical analysis of the hybridization scores according to the fertility status of subjects showed that, compared to normal fertile women, fertile women with endometriosis had decreased expression of IL-1RII mRNA, both in the glandular (P = 0.030) and in the stromal (P = 0.018) compartments of endometrial tissue. However, in infertile women with endometriosis, a significant decrease in IL-1RII mRNA expression was observed only in the glands (P = 0.0004) (Table 2).

RT-PCR Analysis of IL-1RII mRNA Expression in the Endometrium

Expression of IL-1RII mRNA in the endometrial tissue was further evaluated by semiquantitative RT-PCR in 8 normal controls and 10 women with endometriosis (stages I and II). A representative RT-PCR and Southern blot analysis of IL-1RII mRNA in the endometrial tissue of women with endometriosis and of normal controls is shown in Figure 3A. Levels of mRNA were significantly lower in the endometriosis group than in the control group (P = 0.0062) (Fig. 3B), which corroborates the in situ hybridization data.



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  		FIG. 3. RT-PCR followed by Southern blot analysis of IL-1RII transcripts in the endometrial tissue. Total RNA samples were extracted from endometrial biopsy samples of women with (n = 10) and of women without (n = 8) endometriosis, then reverse transcribed, amplified with IL-1RII or GAPDH primers, and hybridized with 32P-labeled corresponding probes as described in Materials and Methods. A) Representative Southern blot analysis. Lanes 1 and 2: women with stage I endometriosis, Days 13 and 18 of the menstrual cycle, respectively; lanes 3 and 4: normal women, Days 12 and 16 of the menstrual cycle, respectively. The GAPDH was used as a control. B) The "box and whisker" plot was used to illustrate IL-1RII mRNA levels using semiquantitative RT-PCR. The box delimits values falling between the 25th and the 75th percentiles, and the horizontal line within the box refers to the median scores. **Significant difference between the endometriosis and control groups (P < 0.01)


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our results showed a significant decrease in the levels of IL-1RII mRNA in the endometrium of patients with endometriosis. This was obvious in the stroma but was more significant in the glands as examined by in situ hybridization. Semiquantitative RT-PCR analysis of IL-1RII mRNA levels in the endometrial tissue also showed a significant decrease in women with endometriosis compared to normal women, which corroborates the in situ hybridization data and provides evidence for a profound defect in IL-1RII gene expression in the eutopic endometrium of women with endometriosis. The IL-1RII is synthesized as a membrane-bound receptor that lacks the signal-transducing cytoplasmic domain found in the functional receptor type I [17]. The receptor can be cleaved and shed from the cell surface by the proteolytic action of matrix metalloproteases [30]. Both membrane-bound and soluble forms of IL-1RII can bind to IL-1 and prevent its interaction with the signal-transducing IL-1RI [16]. Our results, demonstrating a significant decrease in IL-1RII mRNA expression in the endometrial tissue of women with endometriosis, reveal a deficiency in the ability of eutopic endometrial cells of these women to down-regulate their response to IL-1. In fact, eutopic endometrial cells of women with endometriosis appeared to be more sensitive to IL-1 compared to those of normal women, and they secreted higher amounts of MCP-1 following stimulation with IL-1 in vitro [14].

In this work, we observed that defective IL-1RII gene expression in the endometrial tissue was significant at stages I and II, but not in more advanced stages (III and IV), of endometriosis. These results point toward a process of cell activation that takes place locally in the intrauterine endometrium at the earliest stages of the disease, and they suggest that endometriosis is more active during its first stages. Available data regarding the correlation between the extent of endometriosis and that of the chronic inflammatory process observed in the peritoneal fluid of patients and in ectopic as well as eutopic endometrial tissue remain controversial. It has been reported that the concentrations of inflammatory cytokines, such as interleukin 8 and RANTES (regulated upon activation, normal T cell expressed and secreted), correlate with the severity of disease [31, 32]. However, other studies have shown that less extensive endometriosis may be more biochemically active than older implants [33], and that peritoneal inflammation is more active during the initial than the advanced stages of the disease [33, 34]. According to Lessey et al. [35], the defect of integrin expression in the eutopic endometrial tissue is inversely related to the stage of endometriosis. Our previous studies showed that in situ expression of MCP-1, a potent chemotactic and activating factor for monocytes and macrophages, in the endometrial tissue was markedly elevated during the initial stages (I and II) of endometriosis and decreased during more advanced stages (III and IV). Interestingly, we also showed that defective IL-1RII protein expression in the endometrial tissue was more marked during the early stages of the disease [25], which is in keeping with the findings of the present study, and we also found a significant negative correlation with MCP-1 expression in the same tissues [36].

The data of the present study suggest that the reduced expression of IL-1RII in the uterine endometrium of women with endometriosis is related, at least in part, to a defect at the mRNA level, although translational or proteolysis-dependent mechanisms cannot be excluded. However, whether such a defect is due to decreased mRNA synthesis or reduced mRNA stability is unclear. It is also noteworthy to add that the decrease in mRNA levels in the endometrial tissue of women with endometriosis was more significant during the proliferative than the secretory phase of the menstrual cycle, which again is consistent with the cycle-dependent pattern of deficient IL-1RII protein expression [25]. The mechanisms underlying that cycle-dependent, aberrant IL-1RII expression remain unknown. However, this may have an interesting significance, because it suggests that endometrial tissue debris refluxed into the peritoneal cavity at the end of the menstrual cycle may contain low levels of IL-1RII, which may make the tissue less capable of down-regulating IL-1-mediated cell activation and lead to an exaggerated peritoneal inflammatory response.

The data of the present study also suggest that defective IL-1RII expression during the early stages of endometriosis may play a role in the initiation of the immunoinflammatory process eutopically, in the uterine endometrium where the disease is believed to originate, and ectopically, in the peritoneal cavity where endometrial tissue is refluxed and developed. The lack of statistically significant difference in IL-1RII expression between women with and women without endometriosis during the late stages of the disease may, on the other hand, be part of the counterregulatory or reparative mechanisms that stabilize endometriosis by limiting chronic inflammation and profound tissue damage by restricting IL-1-mediated proinflammatory actions [3, 4]. It is interesting to note that Mori et al. [10] demonstrated that the expression of IL-1ß by peritoneal macrophages was elevated during the initial stages of endometriosis and that IL-1ra, another natural specific inhibitor for IL-1, was more elevated during the late stages of the disease.

In conclusion, our results demonstrate that the expression of IL-1RII mRNA was decreased in the endometrium of women with endometriosis, particularly during the initial stages of the disease. Such a defective IL-1RII gene expression by endometrial cells points toward a profound defect in the capability of endometrial cells to down-regulate IL-1 actions, which may play a relevant role in the initiation of the immunoinflammatory process associated with endometriosis, both in the intrauterine endometrium and in the peritoneal cavity following tubal reflux. It remains, however, to be determined whether such a defect is due to transcriptional and/or posttranscriptional events.


   ACKNOWLEDGMENTS
 
The authors wish to thank Dr. Paola Bossù, Department of Biotechnoloy, Research Center Dompé SpA, L'Aquila, Italy, for providing IL-1RII cDNA; Drs. François Belhumeur, Jacques Bergeron, Jean Blanchet, Marc Bureau, Simon Carrier, Elphège Cyr, Marlène Daris, Jean-Louis Dubé, Jean-Yves Fontaine, Céline Huot, Pierre Huot, Johanne Hurtubise, Philippe Laberge, André Lemay, Rodolphe Maheux, Jacques Mailloux, Antonin Rochette, and Marc Villeneuve for patient evaluation and for providing endometrial biopsy samples; Madeleine Desaulniers, Monique Longpré, Johanne Pelletier, and Sylvie Pleau for technical assistance; and Dr. Lucile Turcot-Lemay for help in statistical analysis.


   FOOTNOTES
 
First decision: 5 July 2001.

1 Supported by grant MOP-14638 to A.A. from the Canadian Institutes of Health Research. A.A. is a "Chercheur-Boursier Senior" of the "Fonds de la Recherche en Santé du Québec (FRSQ)." Back

2 Correspondence: Ali Akoum, Laboratoire d'Endocrinologie de la Reproduction, Centre de Recherche, Hôpital Saint-François d'Assise, 10 Rue de l'Espinay, Local D0-711, Québec, PQ, Canada G1L 3L5. FAX: 418 525 4195; ali.akoum{at}crsfa.ulaval.ca Back

Accepted: September 20, 2001.

Received: June 14, 2001.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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