Molecular Human Reproduction, Vol. 6, No. 10, 929-933,
October 2000
© 2000 European Society of Human Reproduction and Embryology
Uterine physiology |
Increased concentrations of soluble tumour necrosis factor receptor (sTNFR) I and II in peritoneal fluid from women with endometriosis
1 Department of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, and 2 CREST, Japan Science and Technology, Kawaguchi 332-0012, Japan
Abstract
Tumour necrosis factor 
(TNF), a proapoptotic cytokine, is known to be present in peritoneal fluid from women with endometriosis. An emerging view is that soluble TNF receptors (sTNFR) can modulate the effects of TNF by acting as TNF antagonists. To assess the relevance of sTNFRs in the pathophysiology of endometriosis, concentrations of sTNFR I, sTNFR II and TNF in peritoneal fluid from women with endometriosis (n = 53) and without endometriosis (n = 40) were measured. Concentrations of both sTNFR I and sTNFR II in peritoneal fluid from women with endometriosis were significantly higher than in peritoneal fluid from women without endometriosis, both in the follicular and the luteal phases. TNF concentrations did not differ in patients with and without endometriosis in both phases. When stratified by the stage of the disease, women with both stages I/II and stages III/IV exhibited significantly higher concentrations of sTNFR I and sTNFR II in peritoneal fluid, compared with women without endometriosis, whereas no appreciable difference in the concentrations was detected between stages I/II and stages III/IV. A significant correlation was found between the concentrations of sTNFR I and sTNFR II; while the correlations between TNF and sTNFR I or sTNFR II, were either not significant or were very weak. Furthermore, mRNA for the membrane-associated TNF receptor type 1 and TNF receptor type 2, both of which convey the effects of TNF, were shown to be expressed in endometriotic tissues as well as eutopic endometrium. Together, these findings suggest a possible involvement of sTNFRs in the pathophysiology of endometriosis.
endometriosis/infertility/peritoneal fluid/soluble TNF receptor/TNF
Introduction
Endometriosis, defined by the presence of endometrium-like tissues outside the uterus, remains to be an enigmatic disease. Although the precise pathogenesis of endometriosis has not been elucidated, a widely-accepted hypothesis is that of retrograde menstrual flux with subsequent implantation and growth of viable endometrial cells in the peritoneal cavity (Sampson, 1927
). Multiple lines of evidence have suggested that both the cellular components and the biochemical constituents of peritoneal fluid play an important role in the pathogenesis of endometriosis (Halme et al., 1988; Koutsilieris et al., 1991). In this regard, a multitude of cytokines and growth factors have been postulated as being implicated in the development and progression of the disease (Ho et al., 1997).
Tumour necrosis factor (TNF) is known to have a wide variety of biological actions (Bazzoni and Beutler, 1996). The expression of TNF has been detected in various reproductive organs including the ovaries (Roby et al., 1990), the oviduct (Hunt, 1993), the endometrium and preimplantation embryos (Zolti et al., 1991; Sharkey et al., 1995), thus implicating TNF in reproduction. Of note, the expression of TNF has been shown to be menstrual cycle-related and the presence of TNF receptors has been demonstrated in human endometrium (Hunt et al., 1992; Philippeaux and Piguet, 1993; Tabibzadeh et al., 1995a,b; Chegini et al., 1999; von Wolff et al., 1999).
TNF exerts its actions through its type 1 and type 2 receptors, which are encoded by two independent genes. Recently, soluble TNF receptors (sTNFR) have gained recognition as bioactive substances which the modulate functions of TNF by specifically antagonizing TNF (Higuchi and Aggarwal, 1992; Mohler et al., 1993; Stewart and Marsden, 1995). A review of the literature indicates the presence of two species of soluble receptors for TNF, i.e. sTNFR I and sTNFR II, which are derived from the extracellular portions of membrane-associated type 1 and type 2 TNF receptors respectively. Soluble TNF receptors are present in a variety of body fluids including serum, urine, cerebrospinal fluid (Tsukada et al., 1993) and peritoneal fluid (Onsrud et al., 1995).
With this background, together with a possible involvement of TNF in the pathophysiology of endometriosis, we determined the concentrations of both TNF and sTNFRs in order to investigate their roles in the development of this disease.
Materials and methods
A total of 93 women with (n = 53) and without (n = 40) endometriosis aged 24–38 years who were undergoing laparoscopy for pain and/or infertility were included in this study. All the women had normal menstrual cycles. Endometriosis was diagnosed both laparoscopically and histologically. The extent of the disease was evaluated according to the revised American Fertility Society classification (American Fertility Society, 1985). The distribution of the stage of endometriosis was: stage I, n = 12; stage II, n = 7; stage III, n = 15; and stage IV, n = 19. In the non-endometriosis group, 16 women were in the follicular phase and 24 in the luteal phase. In the endometriosis group, 27 women were in the follicular phase and 26 in the luteal phase. The age of women in the endometriosis group was 31.9 ± 4.5 years (mean ± SD), which was essentially the same as that of women in the non-endometriosis group (32.4 ± 4.8 years).
Concentrations of sTNFR I, sTNFR II and TNF in peritoneal fluid were measured in duplicate, using a specific enzyme-linked immunsorbent assay (ELISA) in a blind fashion (R&D Systems Inc, Minneapolis, MN, USA). The sensitivity limits of these ELISAs was 7.8 pg/ml per sample for both sTNFR I and sTNFR II, and 0.5 pg/ml per sample for TNF. The intra- and inter-assay coefficients of variation were <10% for each of the three measurements.
In order to detect TNFR type1 and TNFR type2 mRNA, six eutopic endometria (three from women with endometriosis and three from women without endometriosis) and three endometriotic tissues were obtained under laparoscopy. Total RNA was extracted and 1 µg was reverse-transcribed (RT) in a 20 µl volume using TaKaRa RNA PCR kit (Takara Shuzo, Tokyo, Japan), according to the manufacturer's instructions. The reaction mixture (5 µl) was used for polymerase chain reaction (PCR) with the following primers.
For TNFR type 1: 5'-ATT TGC TGT ACC AAG TGC CAC AAA GGA ACC-3' (sense primer, corresponding to nucleotides 323–352 of the published sequence; Gray et al., 1990), and
5'-GTC GAT TTC CCA CAA ACA ATG GAG TAG AGC-3' (antisense primer, corresponding to nucleotides 880–909)
For TNFR type 2: 5'-GAA TAC TAT GAC CAG ACA GCT CAG ATG TGC-3' (sense primer, corresponding to nucleotides 222–251 of the published sequence; Kohno et al., 1990), and
5'-TAT CCG TGG ATG AAG TCG TGT TGG AGA ACG-3', antisense primer (nucleotides 593–624).
A total of 30 cycles were performed, each consisting of 96°C for 2 min, 55°C for 1.5 min and 72°C for 2 min. An aliquot of the reaction was then analysed by agarose gel electrophoresis. The sizes of the predicted product are 587 bp for TNFR type 1 and 403 bp for TNFR type 2. For both PCR procedures, negative controls (i.e. without cDNA or primers) were negative for amplification.
The data were described as median (interquartile range, IQR). Statistical significance was determined using the Mann–Whitney test. Correlation analysis was performed with linear regression analysis; P < 0.05 was considered to be statistically significant.
Results
The concentrations of sTNFR I, sTNFR II and TNF for all the peritoneal fluid samples were above the assay limit. The median concentrations of sTNFR I (3.41 ng/ml; 2.51–5.02) and sTNFR II (5.06 ng/ml; 3.89–7.21) were >1000-fold higher than those of TNF (2.79 pg/ml; 2.17–4.43).
Figure 1 illustrates the distribution of concentrations of sTNFR I, sTNFR II and TNF in peritoneal fluids of women stratified according to the menstrual phase and the presence or absence of endometriosis. When the analysis was restricted to the follicular phase, concentrations of sTNFR I in peritoneal fluids from women with endometriosis (4.45 ng/ml, 3.29–5.88) were significantly higher than those in women without endometriosis (3.41 ng/ml, 2.16–4.28; P = 0.04). Similarly, sTNFR I concentrations in the luteal phase were significantly higher in women with endometriosis (3.63 ng/ml, 2.79–5.65), compared with those without endometriosis (2.67 ng/ml, 2.03–3.08, P = 0.0004). Similarly, sTNFR II concentrations in women with endometriosis were significantly higher than those without endometriosis in both follicular and luteal phases (follicular: 7.11 ng/ml, 4.97–9.42 compared with 4.88 ng/ml, 2.60–6.03, P = 0.002; luteal: 5.66 ng/ml, 4.23–8.83 compared with 4.34 ng/ml, 3.26–4.92, P = 0.012). The concentrations of TNF were not significantly different in samples from women with or without endometriosis in both phases.
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The concentrations of sTNFR I, sTNFR II and TNF
in peritoneal fluids did not differ significantly between the follicular and luteal phases either in women with endometriosis and in those without endometriosis. Thus, in the subsequent analysis, we dealt with the data from both phases as one homogenous group.
Women with both stages I/II and stages III/IV exhibited significantly higher concentrations of sTNFR I and sTNFR II in peritoneal fluids (sTNFR I: stages I/II, 4.27 ng/ml, 3.23–4.80, P = 0.002; stages III/IV, 4.21 ng/ml, 3.01–6.01, P < 0.0001; sTNFR II: stages I/II, 6.05 ng/ml, 4.30–8.21, P = 0.005; stages III/IV, 6.41 ng/ml, 4.69–10.34, P < 0.0001), compared with women without endometriosis (sTNFR I: 2.83 ng/ml, 2.09–3.54; sTNFR II, 4.47 ng/ml, 3.13–5.57) (Figure 2). However, the concentrations of sTNFR I and sTNFR II did not differ between stages I/II and stages III/IV.
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Correlations between the concentrations of sTNFR I, sTNFR II and TNF
are shown in Table I. A strong significant correlation was found between the concentrations of sTNFR I and sTNFR II with a correlation coefficient of 0.775 (Figure 3). The concentrations of TNF did not correlate significantly with sTNFR I concentrations, whereas a significant (but very weak) correlation was found between the concentrations of sTNFR II and TNF.
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As depicted in Figure 4
, RT–PCR products from total RNAs extracted from both endometriotic tissue and eutopic endometrium showed a clear single band for TNFR type 1 at 587 bp and for TNFR type 2 at 403 bp, consistent with their predicted sizes. mRNA for both types of receptors were expressed in all the samples examined.
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Discussion
In the present study, we demonstrated that concentrations of sTNFRs in peritoneal fluid were elevated in women with endometriosis compared with those without endometriosis. On the other hand, no significant difference in TNF concentrations was detected between women with or without endometriosis even when stratified by phase of the menstrual cycle. In the light of recent evidence on the importance of soluble receptors for cytokines in various physiological settings or in the pathophysiology of various diseases (Diez-Ruiz et al., 1995; Dinarello, 1998; Keul et al., 1998; Nelson and Willerford, 1998; Hampel et al., 1999), it is tempting to speculate that sTNFRs in peritoneal fluid may have a role in the pathogenesis of endometriosis.
TNF has been shown to induce apoptosis in both an endometrial epithelial cell line and in glandular epithelial cells derived from normal human endometria (Tabibzadeh et al., 1994). In view of an increase in the amounts of TNF in the endometrium during the secretory and the menstrual phases, TNF is suggested to be proapoptotic in the menstrual endometrium (Tabibzadeh, 1996). With regard to pathogenesis of endometriosis, a widely held theory is that of `implantation' which maintains that endometriosis originates from the uterine endometrium that is transported to ectopic locations via retrograde menstruation. It has been suggested that the failure to eliminate implanted endometrial cells possibly due to abnormalities of the immune system may be conducive to the development of endometriosis. In this context, apoptosis was recently suggested to be important in eliminating influxed endometrial cells, while a decreased susceptibility of endometrial cells to apoptosis could contribute to the aetiology of endometriosis (Harada et al., 1996; Dmowski et al., 1998; Gebel et al., 1998). In the present study, we demonstrated an increase in sTNFRs concentrations in peritoneal fluid from women with endometriosis while there were no discernible differences in TNF concentrations in women either with or without endometriosis. Given the suggested proapoptotic role of TNF, elevated concentrations of sTNFRs in women with endometriosis may antagonize TNF in peritoneal fluid, and consequently attenuate the apoptotic process of influxed endometrial cells in the peritoneal cavity. The observed expression of TNFR type 1 and TNFR type 2 (which transduce the effects of TNF in both endometriotic tissues and eutopic endometrium) may favour this contention.
The mechanisms regulating sTNFRs in peritoneal fluid are unknown. Peritoneal mesothelial cells, neutrophils, activated T cells and monocytes have been reported to secrete sTNFRs under the control of different stimulants including various cytokines (Crowe et al., 1993; Lantz et al., 1994; Leeuwenberg et al., 1994; Douvdevani et al., 1996). In women with endometriosis, the concentrations of various cytokines have been reported to be increased in peritoneal fluid (Giudice et al., 1998). Furthermore, our data provide evidence for a significant positive correlation between the concentrations of sTNFR I and sTNFR II in peritoneal fluid (a situation similar to that in the amniotic fluid; Austgulen et al., 1993) and in the sera from patients with sepsis (Schroder et al., 1995) and rheumatoid arthritis (Robak et al., 1998). Collectively, both sTNFRs are suggested to be under common regulatory mechanisms, and their up-regulation in peritoneal fluid with endometriosis is possibly by elevated cytokine concentrations. On the other hand, TNF concentrations exhibited no correlation with sTNFR I and only a weak correlation with sTNFR II in peritoneal fluid, implying that differential regulatory mechanisms may exist for TNF and sTNFRs.
To date, several studies have found higher TNF concentrations in peritoneal fluid from women with endometriosis compared with women without endometriosis (Eisermann et al., 1988; Ho et al., 1996; Harada et al., 1997). However, some studies have shown contradictory data indicating that no difference was detected between women with and without endometriosis (Vercellini et al., 1993; Keenan et al., 1995; Skrzypczak et al., 1995). In the present study, no significant difference in TNF concentrations in peritoneal fluid was detected even when stratified by menstrual cycle. One possible reason for this discrepancy might be that backgrounds of subjects tested were different among the studies. In a study (Halme et al., 1989), comparing TNF concentrations in women with and without endometriosis, the women without endometriosis were subdivided into those who were fertile and those exhibiting unexplained infertility. Interestingly, a significant difference was found in TNF activity in peritoneal fluid only between women with endometriosis and fertile women without endometriosis, but no difference between women with endometriosis and those with unexplained infertility. The present results, which showed no difference between the endometriosis and non-endometriosis groups might be, in part, ascribable to the fact that most of the non-endometriosis women studied were infertile patients.
In summary, we demonstrated increases in sTNFR I and sTNFR II concentrations in peritoneal fluid from women with endometriosis compared with those without endometriosis, while TNF concentrations are comparable. These findings may indicate a possible contribution of sTNFRs to the development of endometriosis through modulation of TNF-mediated biological effects in the peritoneal cavity.
Acknowledgments
We would like to thank Drs R.Matsuoka, K.Koda and K.Naritaka for their co-operation in the collection of specimens. We also thank Yuko Kai for her technical assistance. This study was supported in part by the Special Co-ordination Funds for Promoting Science and Technology of the Science and Technology Agency of the Japanese Government.
Notes
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan. E-mail: taketani-tky{at}umin.ac.jp 
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Submitted on March 31, 2000; accepted on July 19, 2000.
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