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• W85930945 abstract "Endometriosis is often associated with a chronic pelvic immuno-inflammatory process, which is closely related to disease pathogenesis and major symptoms. Our studies led to the detection of a marked imbalance between IL-1 and its natural inhibitor IL-1 receptor type 2 (IL1R2) in women with endometriosis. This points to a deficiency in the local control of IL-1 that, in view of the cytokine's elevated levels and potent proinflammatory, angiogenic, and growth-promoting effects, may contribute to endometriosis development. Using an in vivo model in which human endometrial tissue was inoculated into nude mice and left to establish before any further treatment, our data showed that sIL1R2 interferes with the capability of endometrial tissue to invade, grow, disseminate, and stimulate angiogenesis into the host tissue. sIL1R2 significantly down-regulated the expression of major cell adhesion receptors (αv and β3 integrins), matrix metalloproteinases (MMP-2 and -9), and vascular endothelial cell growth factor. Interestingly, treatment with sILR2 (5 μg/kg) led to a concomitant upregulation of matrix metalloproteinases natural inhibitors (TIMP1 and TIMP2) and down-regulation of BclII, a potent anti-apoptotic protein. This creates an imbalance between pro- and anti-proteolytic and apoptotic factors and may further contribute to IL1R2 growth-inhibitory effects. This study provides evidence that sIL1R2 alters ectopic endometrial tissue growth, remodeling, and survival in vivo and may represent an interesting potential therapeutic tool. Endometriosis is often associated with a chronic pelvic immuno-inflammatory process, which is closely related to disease pathogenesis and major symptoms. Our studies led to the detection of a marked imbalance between IL-1 and its natural inhibitor IL-1 receptor type 2 (IL1R2) in women with endometriosis. This points to a deficiency in the local control of IL-1 that, in view of the cytokine's elevated levels and potent proinflammatory, angiogenic, and growth-promoting effects, may contribute to endometriosis development. Using an in vivo model in which human endometrial tissue was inoculated into nude mice and left to establish before any further treatment, our data showed that sIL1R2 interferes with the capability of endometrial tissue to invade, grow, disseminate, and stimulate angiogenesis into the host tissue. sIL1R2 significantly down-regulated the expression of major cell adhesion receptors (αv and β3 integrins), matrix metalloproteinases (MMP-2 and -9), and vascular endothelial cell growth factor. Interestingly, treatment with sILR2 (5 μg/kg) led to a concomitant upregulation of matrix metalloproteinases natural inhibitors (TIMP1 and TIMP2) and down-regulation of BclII, a potent anti-apoptotic protein. This creates an imbalance between pro- and anti-proteolytic and apoptotic factors and may further contribute to IL1R2 growth-inhibitory effects. This study provides evidence that sIL1R2 alters ectopic endometrial tissue growth, remodeling, and survival in vivo and may represent an interesting potential therapeutic tool. Endometriosis is a serious gynecological pathologic condition and a major public health concern in view of its physical, psychological, and socioeconomic impacts. This disease affects 6% to 10% of reproductive-aged women, 50% to 60% of teenage girls with pelvic pain, and up to 50% of women with infertility.1Giudice L.C. Clinical practice Endometriosis.N Engl J Med. 2010; 362: 2389-2398Crossref PubMed Scopus (1296) Google Scholar, 2Holoch K.J. Lessey B.A. Endometriosis and infertility.Clin Obstet Gynecol. 2010; 53: 429-438Crossref PubMed Scopus (123) Google Scholar Endometriosis is estrogen dependent; however, several risk factors are thought to contribute to the pathogenesis of the disease. Abundant menstrual reflux and early menarche,3Cramer D. Wilson E. Stillman F. Berger M. Belisle S. Schiff I. Albrechts B. Gibsin M. Stadel B. Shoenbaum S. The relation of endometriosis to menstrual characteristics smoking and exercice.JAMA. 1986; 255: 1904-1908Crossref PubMed Scopus (304) Google Scholar genetic and environmental factors,4Painter J.N. Anderson C.A. Nyholt D.R. Macgregor S. Lin J. Lee S.H. Lambert A. Zhao Z.Z. Roseman F. Guo Q. Gordon S.D. Wallace L. Henders A.K. Visscher P.M. Kraft P. Martin N.G. Morris A.P. Treloar S.A. Kennedy S.H. Missmer S.A. Montgomery G.W. Zondervan K.T. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis.Nat Genet. 2011; 43: 51-54Crossref PubMed Scopus (246) Google Scholar, 5Simpson J.L. Elias S. Malinak L.R. Buttram Jr, V.C. Heritable aspects of endometriosis I. Genetic studies.Am J Obstet Gynecol. 1980; 137: 327-331Abstract Full Text PDF PubMed Scopus (381) Google Scholar, 6Rier S.E. Martin D.C. Bowman R.E. Dmowski W.P. Becker J.L. Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.Fundam Appl Toxicol. 1993; 21: 433-441Crossref PubMed Scopus (393) Google Scholar, 7Anger D.L. Foster W.G. The link between environmental toxicant exposure and endometriosis.Front Biosci. 2008; 13: 1578-1593Crossref PubMed Scopus (49) Google Scholar hormonal dysfunctions,8Zeitoun K.M. Bulun S.E. Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target.Fertil Steril. 1999; 72: 961-969Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar and impaired immune response have been suggested.9Cakmak H. Guzeloglu-Kayisli O. Kayisli U.A. Arici A. Immune-endocrine interactions in endometriosis.Front Biosci. 2009; 1: 429-443Google Scholar, 10Bondza P.K. Maheux R. Akoum A. Insights into endometriosis-associated endometrial dysfunctions: a review.Front Biosci. 2009; 1: 415-428PubMed Google Scholar The most predominant hypothesis defines endometriosis as an abnormal implantation of endometrial tissue outside the uterus, mainly in the peritoneal cavity.11Sampson J.A. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation.Am J Pathol. 1927; 3: 93-110143PubMed Google Scholar This is supported by a growing body of evidence corroborating our first data and showing the intrinsic capability of endometrial tissue to invade, implant, and grow into the host tissue, and a significant contribution of immune factors to the development of endometriosis and its major clinical symptoms.10Bondza P.K. Maheux R. Akoum A. Insights into endometriosis-associated endometrial dysfunctions: a review.Front Biosci. 2009; 1: 415-428PubMed Google Scholar, 12Akoum A. Lemay A. Brunet C. Hebert J. Secretion of monocyte chemotactic protein-1 by cytokine-stimulated endometrial cells of women with endometriosis Le Groupe d'Investigation en Gynecologie.Fertil Steril. 1995; 63: 322-328Abstract Full Text PDF PubMed Scopus (90) Google Scholar Endometriosis is often associated with a chronic pelvic immunoinflammatory reaction.1Giudice L.C. Clinical practice Endometriosis.N Engl J Med. 2010; 362: 2389-2398Crossref PubMed Scopus (1296) Google Scholar Autoantibodies nonspecific or specific to endometrial antigens have been found in the peritoneal fluid of patients along with an increased recruitment of proinflammatory cells, especially activated macrophages, and higher levels of reactive oxygen species, proteolysis enzymes, prostaglandins, and proinflammatory cytokines.10Bondza P.K. Maheux R. Akoum A. Insights into endometriosis-associated endometrial dysfunctions: a review.Front Biosci. 2009; 1: 415-428PubMed Google Scholar, 13Akoum A. Al-Akoum M. Lemay A. Maheux R. Leboeuf M. Imbalance in the peritoneal levels of interleukin 1 and its decoy inhibitory receptor type II in endometriosis women with infertility and pelvic pain.Fertil Steril. 2008; 89: 1618-1624Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 14Akoum A. Lemay A. McColl S. Turcot-Lemay L. Maheux R. Elevated concentration and biologic activity of monocyte chemotactic protein-1 in the peritoneal fluid of patients with endometriosis.Fertil Steril. 1996; 66: 17-23PubMed Google Scholar, 15Kats R. Collette T. Metz C.N. Akoum A. Marked elevation of macrophage migration inhibitory factor in the peritoneal fluid of women with endometriosis.Fertil Steril. 2002; 78: 69-76Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 16Keenan J.A. Chen T.T. Chadwell N.L. Torry D.S. Caudle M.R. IL-1 beta. TNF-alpha, and IL-2 in peritoneal fluid and macrophage-conditioned media of women with endometriosis.Am J Reprod Immunol. 1995; 34: 381-385Crossref PubMed Scopus (155) Google Scholar, 17Mori H. Sawairi M. Nakagawa M. Itoh N. Wada K. Tamaya T. Peritoneal fluid interleukin-1 beta and tumor necrosis factor in patients with benign gynecologic disease.Am J Reprod Immunol. 1991; 26: 62-67Crossref PubMed Scopus (110) Google Scholar IL-1 is a major proinflammatory cytokine that exerts its biological effects via the IL-1 receptor type 1 (IL1R1), the signaling receptor. IL-1 is regulated by IL-1 receptor antagonist (IL1RA) by competing for binding to ILR1. This control system is consolidated by another potent, specific, and natural IL-1 inhibitor, IL-1 receptor type 2 (IL1R2). This decoy receptor has no signaling properties. It instead counterregulates IL-1 signaling by sequestrating active and inactive IL-1, thereby restricting the cytokine's bioavailability and effects. Interestingly, both the membrane-bound receptor and the soluble form (sIL1R2), which results from a proteolytic cleavage form IL1R2 extracellular domain, can bind to and capture IL-1.18Orlando S. Sironi M. Bianchi G. Drummond A.H. Boraschi D. Yabes D. Mantovani A. Role of metalloproteases in the release of the IL-1 type II decoy receptor.J Biol Chem. 1997; 272: 31764-31769Crossref PubMed Scopus (97) Google Scholar, 19Colotta F. Dower S.K. Sims J.E. Mantovani A. The type II ‘decoy’ receptor: a novel regulatory pathway for interleukin 1.Immunol Today. 1994; 15: 562-566Abstract Full Text PDF PubMed Scopus (329) Google Scholar, 20Bossu P. Visconti U. Ruggiero P. Macchia G. Muda M. Bertini R. Bizzarri C. Colagrande A. Sabbatini V. Maurizi G. Del Grosso E. Tagliabue A. Boraschi D. Transfected type II interleukin-1 receptor impairs responsiveness of human keratinocytes to interleukin-1.Am J Pathol. 1995; 147: 1852-1861PubMed Google Scholar Our and other recent studies have led to the detection of an imbalance between IL-1 and sIL1R2 in the peritoneal fluid of patients with endometriosis, where a significant decrease in the levels of IL1R2 and a concomitant increase in those of IL-1 were noted13Akoum A. Al-Akoum M. Lemay A. Maheux R. Leboeuf M. Imbalance in the peritoneal levels of interleukin 1 and its decoy inhibitory receptor type II in endometriosis women with infertility and pelvic pain.Fertil Steril. 2008; 89: 1618-1624Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 21Kondera-Anasz Z. Sikora J. Mielczarek-Palacz A. Jonca M. Concentrations of interleukin (IL)-1alpha. IL-1 soluble receptor type II (IL-1 sRII) and IL-1 receptor antagonist (IL-1 Ra) in the peritoneal fluid and serum of infertile women with endometriosis.Eur J Obstet Gynecol Reprod Biol. 2005; 123: 198-203Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar This was quite obvious in initial endometriosis stages and is consistent with the marked down-regulation of IL1R2 protein and mRNA expression in the earliest and most active endometriotic lesions.22Akoum A. Lawson C. Herrmann-Lavoie C. Maheux R. Imbalance in the expression of the activating type I and the inhibitory type II interleukin 1 receptors in endometriosis.Hum Reprod. 2007; 22: 1464-1473Crossref PubMed Scopus (38) Google Scholar, 23Lawson C. Bourcier N. Al-Akoum M. Maheux R. Naud F. Akoum A. Abnormal interleukin 1 receptor types I and II gene expression in eutopic and ectopic endometrial tissues of women with endometriosis.J Reprod Immunol. 2008; 77: 75-84Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar These findings point to endometriosis-associated major defects in local IL-1 counterregulatory mechanisms, which, considering IL-1 proinflammatory, remodeling, angiogenic, and growth-promoting effects, may play an important role in the establishment and development of endometriosis. Based on the above-reported evidence, we undertook an in vivo study to investigate the effects of an intraperitoneal administration of sIL1R2 on endometriosis progression using a murine model of endometriosis. Women who were included in this study provided informed consent for a research protocol approved by Saint-François d'Assise Hospital ethics committee. Endometrial tissue was collected using a Pipelle de Cornier (Prodimed, Neuilly-en-Thelle, France) during the proliferative phase (day 2 to day 13) of the menstrual cycle from 10 healthy, normally cycling women (mean ± SD age, 36.2 ± 5.2 years) who were undergoing laparoscopy for benign conditions, did not have endometriosis, and were not receiving anti-inflammatory or hormonal medication for at least 3 months before surgery. A sample of each tissue was kept at −80°C for histological confirmation of the menstrual phase.24Noyes R.W. Hertig A.T. Rock J. Dating the endometrial biopsy.Am J Obstet Gynecol. 1975; 122: 262-263PubMed Scopus (696) Google Scholar The remaining tissue, destined for the in vivo studies, was immediately washed in PBS, dissected into small (1 mm3) cubes, and labeled with a fluorescent tracker, carboxyfluorescein diacetate, succinimidyl ester (CFDA-SE) (8.10−6 M in PBS) (Invitrogen. Burlington, ON, Canada).25Defrere S. Colette S. Lousse J.C. Donnez J. Van Langendonckt A. Review: luminescence as a tool to assess pelvic endometriosis development in murine models.Reprod Sci. 2009; 16: 1117-1124Crossref PubMed Scopus (4) Google Scholar Tissue labeling was confirmed by fluorescence stereomicroscopy. The protocol was approved by the committee of animal protection of Laval University. Five- to 7-week-old female athymic Nude-Foxn1nu mice (Harlan Laboratories, Indianapolis, IN) were used after a 1-week acclimatization period. Mice were housed under laminar-flow filtered hoods at 28°C with a 12:12-hour light-dark cycle. Housing materials, food, and water were sterilized before use. Animals were given buprenorphine (1.68 g per mouse) by intradermal injection for analgesia, then anesthetized with a mixture of oxygen (1.5: l) and isoflurane (3% to 4%) (Abbot Laboratories, Saint-Laurent, Quebec, Canada). A small (1 cm) cutaneous and peritoneal incision was made in a sterile environment, and 0.1 mL of PBS containing 13 CFDA-labeled endometrial tissue fragments (Figure 1, A and B) was injected into the peritoneal cavity using a micropipette. The incision was closed with Coated NB (polyglactin 910) sutures (Ethicon Johnson & Johnson, Markham, ON, Canada) for the peritoneal tissue and MikRon autoclip 9 mm (Clay Adam Brand, Sparks, MD) for the cutaneous tissue. Implanted mice were monitored daily for comfort, survival, and weight. Ten biopsy samples from 10 different patients were used. Each sample was used to inoculate one control mouse (treated with PBS) and one mouse treated with one of the shIL1R2 doses. Twelve days after tissue injection, animals received a daily intraperitoneal injection of 100 μL of sterile PBS solution (control group, n = 10) or containing 5 or 25 μg/kg shIL1R2 (n = 5 for each group) (R&D Systems, Inc., Minneapolis, MN) and were monitored for survival and weight. Two weeks later, mice were anesthetized with isoflurane/O2 mixture, then euthanized in an atmosphere saturated by CO2 (10 L/min), and the abdominal cavity was examined under a fluorescence stereomicroscope connected to a color CCD HD camera (DAGE-MTI, Michigan City, IN). A detectable signal depends on the brightness of the fluorophore and tissue penetration of both the excitation and emission light. Fluorescence of CFDA SE was detected at χex465/χem535.26Defrere S. Van Langendonckt A. Gonzalez Ramos R. Jouret M. Mettlen M. Donnez J. Quantification of endometriotic lesions in a murine model by fluorimetric and morphometric analyses.Hum Reprod. 2006; 21: 810-817Crossref PubMed Scopus (19) Google Scholar Using these excitation/emission wavelengths and fluorescence filters, labeled tissue was detected without noticeable tissue autofluoresecence or background noise. Lesions (Figure 1, C and D) were numbered, measured, and photographed in situ before being collected and stored at −80°C for histological studies using H&E staining, CD10, and cytokeratin immunostaining, and quantitative real-time (qPCR) analyses. Tissue cryosections (5 μm) were rinsed in cold PBS, treated with 3% hydrogen peroxide to block endogenous peroxidase activity, and incubated for 1 hour at room temperature with rabbit polyclonal anti-human cytokeratin 7 antibody (GeneTex, Irvine, CA) [1:100 dilution in PBS/bovine serum albumin (BSA) 3%] and anti-human vimentin (Novus Biologicals, Littleton, CO) (1:100 dilution in PBS/BSA 3%). Sections were then incubated with a peroxidase-conjugated goat anti-rabbit antibody (1:500 dilution in PBS/BSA 3%) (Jackson ImmunoResearch Laboratories, Mississauga, ON, Canada) before being incubated with the peroxidase substrate 3,3′-diaminobenzidine for 5 minutes, rinsed in PBS, counterstained with hematoxylin, and mounted in Mowiol. RNA was extracted with Trizol (Invitrogen), and qPCR was performed using an ABI 7000 Thermal Cycler (Applied Biosystems, Foster City, CA). Each PCR reaction contained 2 μL of reverse transcriptase product, 0.5 μL of primer (final concentration, 0.1 mm), 12.5 μL of SYBR Green PCR Master Mix (Invitrogen) containing TaqDNA polymerase buffer, deoxynucleotide triphosphate mix, SYBR green I, MgCl2, and TaqDNA polymerase. Primers were designed with Primer Premier 5 software to cross intron-exon boundaries and specificity to human tissue was verified with Basic Local Alignment Search Tool (BLAST) (http://blast.ncbi.nlm.nih.gov/Blast.cgi) (Table 1). Samples were tested in duplicate, and, for each reaction, negative controls without RNA or reverse transcriptase, RNA from mouse tissue (negative control), and RNA from endometrial tissue (positive control) were added.Table 1List of PCR PrimersGenePrimersTm (°C)GenBank accession no.BaxF: 5′-TCAACTGGGGCCGGGTTGTC-3′60NM_004324.3R: 5′-CCTGGTCTTGGATCCAGCCCAAC-3′Bcl2F: 5′-GGCACACGCCCCATCCAGCC-3′60NM_000657.2R: 5′-GCCGGGGGCAGCCGGGGTCT-3′GAPDHF: 5′-CAGGGCTGCTTTTAACTCTGG-3′60NM_002046.3R: 5′-TGGGTGGAATCATATTGGAACA-3′Integrin αvF: 5′-GGAGCAATTCGACGAGCACT-3′60NM_001144999.1R: 5′-TTCATCCCGCAGATACGCTA-3′Integrin β3F: 5′-TGACGAAAATACCTGCAACCG-3′60NM_000212.2R: 5′-GCATCCTTGCCAGTGTCCTTAA-3′MMP2F: 5′-TTGACGGTAAGGACGGACTC-3′60NM_001127891.1R: 5′-ACTTGCAGTACTCCCCATCG-3′MMP9F: 5′-TTGACAGCGACAAGAAGTGG-3′60NM_004994.2R: 5′-CCCTCAGTGAAGCGGTACAT-3′TIMP1F: 5′-AAGGCTCTGAAAAGGGCTTC-3′60NM_003254.2R: 5′-GAAAGATGGGAGTGGGAACA-3′TIMP2F: 5′-GAGAAGGAAGTGGACTCTGGAAAC-3′56NM_003255.4R: 5′-AAACTCTATATCCTTCTCAGGCC-3′TIMP3F: 5′-ACATGCTCGCCCAGCCAC-3′60NM_000362.4R: 5′-TGCACATGGGGCATCTTGG-3′VEGFF: 5′-GCTCTACCTCCACCATGCCA-3′60NM_001171630.1R: 5′-CACCACTTCGTGATGATTCTGC-3′F, forward; R, reverse. Open table in a new tab F, forward; R, reverse. Data related to the number and volume of lesions followed a nonparametric distribution and were analyzed using the U-test. Data related to the weight of mice and qPCR followed a Gaussian distribution and were analyzed using the Student's t-test (GraphPad Software, San Diego, CA). Differences were considered as statistically significant for P < 0.05. To first ascertain the effect of tissue inoculation before any treatment and that of shIL1R2 on animal health, we monitored animal body weight and survival rate. As shown in Figure 1, E and F, all inoculated animals survived, but had a higher weight during the first 7 days after inoculation (P < 0.05). However, no weight difference between inoculated and control mice was then observed until day 12, corresponding to the start of treatment. Similarly, all animals survived after daily injection of shIL1R2 (25 μg/kg) for 2 weeks or an equal volume of a vehicle solution (PBS) (Figure 1G). However, animals in both groups showed a slight weight loss during the first 3 days, which, in control mice, reached 91.3% ± 0.5% at the end of treatment but was fully recovered (99.4% ± 0.8%) in shIL1R2-treated mice (Figure 1H). Endometrial tissue was allowed to implant and establish before starting treatment. Histological assessment of implants showed a well-preserved typical endometrial histomorphology comparable to initial endometrial tissue, with stroma surrounding glandular structures and distinguishable from the underneath murine host tissue (Figure 2, A and B). Using this in vivo endometriosis model with established endometrial implants, we next studied the impact of shIL1R2 treatment using two different doses (5 and 25 μg/kg). For each shIL1R2 dose, five mice versus five vehicle-treated mice (controls) were used. In other terms, there were 10 vehicle-treated animals and 5 mice per treatment. It is noteworthy that no significant difference between the control groups was observed, either in the number (mean ± SD, 8.0 ± 4.84 and 8.2 ± 2.58) or in the volume (mean ± SD, 1.89 ± 1.49 and 1.31 ± 0.82) of endometriotic lesions (P = 0.84 and P = 0.11, respectively). Stereomicroscopic identification of fluorescence-labeled endometrial implants showed a recovery rate of 71.0% ± 0.2%. Lesions in shIL1R2-treated mice exhibited an obvious decrease in size as compared with control mice (Figure 3A). Statistical analysis showed that shIL1R2 (5 and 25 μg/kg) exerts a significant inhibitory effect on the development of endometrial implants by decreasing their number (P < 0.05) and total volume (6.6- and 4.8-fold reduction, respectively) (P < 0.001) (Figure 3, B and C). Histological evaluation further showed disrupted structures in lesions from shIL1R2-treated mice, as compared with lesions from vehicle-treated control mice showing well-defined endometrial glands and stroma surrounded by host mouse tissue (Figure 4, A and B). Immunostaining of vimentin and cytokeratins confirmed the presence of endometrial stromal and glandular cells, respectively (Figure 4, C and E).Figure 4Histological evaluation of endometrial implants from mice treated with vehicle (A) or shIL1R2 (B) at sacrifice (magnification, ×10). Endometrial stromal and glandular cells were identified using vimentin (C) and cytokeratin (E) immunostaining. Sections incubated without the primary antibody were used as negative control for immunostaining (D) (original magnification, ×20). ck+, cytokeratin-positive immunostaining; EG, endometrial gland; MT, mouse tissue; vm+, vimentin-positive immunostaining.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Analysis of harvested lesions according to the implantation site showed several invaded organs and tissues in control mice, mainly the intestines, the peritoneum, the liver, and fat tissue, whereas shILR2 treatment appeared to increase the resistance of many organs to invasion by human endometrial implants (Figure 5, A–C). Statistical analysis showed that in mice treated with shIL1R2 (5 and 25 μg/kg), lesion size and number were significantly reduced in these organs and tissues. Furthermore, lesions fully disappeared in the uterus and ovaries (Figure 5, D–I). The development of endometriosis requires an intricate network of biological processes, including cell adhesion, invasion and angiogenesis, which enable endometrial tissue to implant and grow within the host tissue, as well as the deployment of anti-apoptotic mechanisms that favor its ectopic survival. To investigate whether any significant changes in these biological processes may underlie the shIL1R2-induced diminution in the number, size, and dissemination of endometrial implants, the expression of main tissue adhesion, apoptosis, proteolysis, and angiogenesis mediators found to be significantly dysregulated in human endometriotic lesions was assessed. As shown in Figure 6, A and B, treatment with shIL1R2 (5 and 25 μg/kg) led to a significant and dose-dependent down-regulation of the adhesion receptors integrins αv (P < 0.05 and P < 0.001, respectively) and β3 (P < 0.05) in endometrial implants. We then investigated the expression of Bax and Bcl-2, which are two main regulatory proteins of cell apoptosis and survival, respectively. For Bax expression, no statistically significant difference between control lesions and those collected from mice treated with 5 μg/kg shIL1R2 was noted. However, at a higher shIL1R2 dose (25 μg/kg), Bax expression was significantly decreased (P < 0.01) (Figure 6C). As for BclII, the inhibitory effect of shIL1R2 was dose dependent and statistically significant at both shIL1R2 doses (P < 0.001) (Figure 6D). Matrix metalloproteinases play a critical role in the invasive capacity of endometrial implants and the deployment of a new vessel network. Therefore, we analyzed the expression level of MMP-2 and MMP-9, two MMPs found to be up-regulated in active endometriotic lesions and involved in endometriosis development.27Wenzl R.J. Heinzl H. Localization of matrix metalloproteinase-2 in uterine endometrium and ectopic implants.Gynecol Obstet Invest. 1998; 45: 253-257Crossref PubMed Scopus (75) Google Scholar, 28Chung H.W. Wen Y. Chun S.H. Nezhat C. Woo B.H. Lake Polan M. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 mRNA expression in ectopic and eutopic endometrium in women with endometriosis: a rationale for endometriotic invasiveness.Fertil Steril. 2001; 75: 152-159Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 29Chung H.W. Lee J.Y. Moon H.S. Hur S.E. Park M.H. Wen Y. Polan M.L. Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium.Fertil Steril. 2002; 78: 787-795Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 30Bellehumeur C. Collette T. Maheux R. Mailloux J. Villeneuve M. Akoum A. Increased soluble interleukin-1 receptor type II proteolysis in the endometrium of women with endometriosis.Hum Reprod. 2005; 20: 1177-1184Crossref PubMed Scopus (31) Google Scholar The results showed a significant decrease in MMP-2 mRNA levels in mice treated with 5 (P < 0.01) and 25 μg/kg (P < 0.001) of shIL1R2, compared with control mice (Figure 7A). As for MMP-9 mRNA levels, we noted a significant diminution in endometriotic lesions collected from mice treated with 5 (P < 0.05) and 25 μg/kg (P < 0.001) of shIL1R2 in comparison with control lesions (Figure 7B). Furthermore, as the invasive capacity of endometrial tissue depends on the balance between MMPs and their natural tissue inhibitor TIMPs, we further evaluated, in the same endometriotic lesions, the expression level of TIMPs 1, 2, and 3, known for inhibiting MMP-2 and MMP-9 activities.29Chung H.W. Lee J.Y. Moon H.S. Hur S.E. Park M.H. Wen Y. Polan M.L. Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium.Fertil Steril. 2002; 78: 787-795Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 30Bellehumeur C. Collette T. Maheux R. Mailloux J. Villeneuve M. Akoum A. Increased soluble interleukin-1 receptor type II proteolysis in the endometrium of women with endometriosis.Hum Reprod. 2005; 20: 1177-1184Crossref PubMed Scopus (31) Google Scholar Data depicted in Figure 7, C–E, show that shILR2 had a significant dose-dependent impact on TIMP expression. Actually, treatment of mice with 5 μg/kg of shIL1R2 resulted in a significant up-regulation of TIMP1 (P < 0.05) and TIMP2 (P < 0.05) mRNA levels, as compared with vehicle-treated mice, whereas no statistically significant effect on TIMP3 mRNA levels was noted. However, treatment with 25 μg/kg of shIL1R2 rather had a down-regulatory effect on TIMPs 1, 2, and 3 expression (P < 0.01, P < 0.01 and P < 0.001, respectively). Furthermore, treatment with shIL1R2 either at 5 or 25 μg/kg significantly inhibited the expression of vascular endothelial cell growth factor (VEGF), a major angiogenic factor markedly expressed in active, early-stage, and highly vascularized endometriotic lesions31Donnez J. Smoes P. Gillerot S. Casanas-Roux F. Nisolle M. Vascular endothelial growth factor (VEGF) in endometriosis.Hum Reprod. 1998; 13: 1686-1690Crossref PubMed Scopus (457) Google Scholar (P < 0.01) (Figure 7F). This report, for the first time, provides evidence that shIL1R2 can inhibit ectopic endometrial tissue growth and endometriosis progression in vivo. Using a nude mouse model of endometriosis,32Bruner-Tran K.L. Eisenberg E. Yeaman G.R. Anderson T.A. McBean J. Osteen K.G. Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice.J Clin Endocrinol Metab. 2002; 87: 4782-4791Crossref PubMed Scopus (162) Google Scholar, 33Lousse J.C. Defrere S. Van Langendonckt A. Gras J. Gonzalez-Ramos R. Colette S. Donnez J. Iron storage is significantly increased in peritoneal macrophages of endometriosis patients and correlates with iron overload in peritoneal fluid.Fertil Steril. 2009; 91: 1668-1675Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar in which human endometrial tissue was allowed to implant and to establish before any exogenous treatment, our data show that administration of shIL1R2 significantly reduced the number, volume, and dissemination of endometrial implants. Our data also show that shIL1R2 down-regulates the e" @default.
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• W85930945 date "2012-10-01" @default.
• W85930945 modified "2023-10-09" @default.
• W85930945 title "Soluble Human IL-1 Receptor Type 2 Inhibits Ectopic Endometrial Tissue Implantation and Growth" @default.
• W85930945 cites W1506736207 @default.
• W85930945 cites W1513717411 @default.
• W85930945 cites W1521668645 @default.
• W85930945 cites W1662990931 @default.
• W85930945 cites W1977671182 @default.
• W85930945 cites W1978468923 @default.
• W85930945 cites W1979315677 @default.
• W85930945 cites W1980912607 @default.
• W85930945 cites W1983720219 @default.
• W85930945 cites W1986891553 @default.
• W85930945 cites W1993026721 @default.
• W85930945 cites W1994760822 @default.
• W85930945 cites W2004442355 @default.
• W85930945 cites W2005309779 @default.
• W85930945 cites W2006143607 @default.
• W85930945 cites W2011263448 @default.
• W85930945 cites W2011814811 @default.
• W85930945 cites W2012071401 @default.
• W85930945 cites W2015536508 @default.
• W85930945 cites W2029318049 @default.
• W85930945 cites W2029773366 @default.
• W85930945 cites W2032038471 @default.
• W85930945 cites W2041316663 @default.
• W85930945 cites W2042517728 @default.
• W85930945 cites W2055943730 @default.
• W85930945 cites W2056342089 @default.
• W85930945 cites W2057323778 @default.
• W85930945 cites W2058587734 @default.
• W85930945 cites W2059671018 @default.
• W85930945 cites W2078814319 @default.
• W85930945 cites W2078950332 @default.
• W85930945 cites W2080802473 @default.
• W85930945 cites W2085585495 @default.
• W85930945 cites W2097989839 @default.
• W85930945 cites W2104244553 @default.
• W85930945 cites W2104653323 @default.
• W85930945 cites W2107925338 @default.
• W85930945 cites W2113444126 @default.
• W85930945 cites W2113913813 @default.
• W85930945 cites W2118395124 @default.
• W85930945 cites W2121492292 @default.
• W85930945 cites W2125576226 @default.
• W85930945 cites W2130254982 @default.
• W85930945 cites W2140246703 @default.
• W85930945 cites W2143299448 @default.
• W85930945 cites W2147348949 @default.
• W85930945 cites W2161033554 @default.
• W85930945 cites W2165789728 @default.
• W85930945 cites W2170554336 @default.
• W85930945 cites W2204640292 @default.
• W85930945 cites W2411029809 @default.
• W85930945 cites W2418067841 @default.
• W85930945 cites W2418373307 @default.
• W85930945 cites W2985833654 @default.
• W85930945 cites W3125897090 @default.
• W85930945 cites W4296992478 @default.
• W85930945 cites W4313333738 @default.
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