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• W2085484171 abstract "Endometriosis is characterized by pelvic inflammation that shows an increased number of activated peritoneal macrophages and their secreted products such as cytokines, growth factors, and angiogenic factors. Our results show that activation of nuclear factor-kappa B (NF-κB), a pro-inflammatory transcription factor, is statistically significantly increased in peritoneal macrophages from patients with endometriosis when compared with controls. Endometriosis is characterized by pelvic inflammation that shows an increased number of activated peritoneal macrophages and their secreted products such as cytokines, growth factors, and angiogenic factors. Our results show that activation of nuclear factor-kappa B (NF-κB), a pro-inflammatory transcription factor, is statistically significantly increased in peritoneal macrophages from patients with endometriosis when compared with controls. Endometriosis is a gynecologic disorder characterized by the proliferation of endometrial glands and stroma outside the uterine cavity. Retrograde menstruation, peritoneal adhesion, and outgrowth of endometrial tissue are essential to the pathogenesis of endometriosis according to Sampson's classic implantation theory (1Sampson J.A. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity.Am J Obstet Gynecol. 1927; 14: 422-469Abstract Full Text PDF Google Scholar). However, the stimuli promoting attachment and outgrowth of endometrial cells upon their arrival in the peritoneal cavity are unknown. The peritoneal environment appears to play a major role in the pathogenesis of pelvic endometriosis. It is widely accepted that local inflammation occurs in the peritoneal cavity, which is characterized by several changes to the immunologic components and inflammatory mediators in peritoneal fluid. In particular, peritoneal macrophages have been identified as key cells in the regulation and promotion of this pelvic inflammatory process. Indeed, pelvic macrophage numbers and concentrations are enhanced in the peritoneal fluid of patients with endometriosis and are more strongly activated in case of endometriosis (2Oral E. Olive D.L. Arici A. The peritoneal environment in endometriosis.Hum Reprod Update. 1996; 2: 385-398Crossref PubMed Scopus (168) Google Scholar, 3Halme J. Becker S. Wing R. Accentuated cyclic activation of peritoneal macrophages in patients with endometriosis.Am J Obstet Gynecol. 1984; 148: 85-90Abstract Full Text PDF PubMed Scopus (190) Google Scholar). Peritoneal macrophages can remove erythrocytes, damaged tissue fragments, and probably endometrial cells that gain access to the pelvic cavity. Endometriosis may develop when the scavenging systems are overwhelmed by excessive amounts of retrograde menstruation or when a defective peritoneal scavenging system allows implantation and growth of endometrial cells (4Dunselman Peritoneal environment in endometriosis.in: Shaw R.W. Endometriosis: current understanding and management. Blackwell Science, Oxford1995: 47-74Google Scholar, 5Vinatier D. Cosson M. Dufour P. Is endometriosis an endometrial disease?.Eur J Obstet Gynecol Reprod Biol. 2000; 91: 113-125Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). Once activated, macrophages may express nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and release a wide range of factors such as cytokines (including interleukin-1 [IL-1], IL-6, IL-8, IL-10, IL-12, IL-13, and tumor necrosis factor-α [TNF-α]), growth factors, and angiogenic factors (vascular endothelial growth factor and platelet-derived growth factor). These products are involved in the initiation, maintenance, and progression of endometriosis by inducing endometrial fragment adhesion, proliferation, and neovascularization (6Lebovic D.I. Mueller M.D. Taylor R.N. Immunology of endometriosis.Fertil Steril. 2001; 75: 1-10Abstract Full Text Full Text PDF PubMed Scopus (665) Google Scholar). Nuclear factor-kappa B (NF-κB) is a transcriptional factor that plays a crucial role in inflammation, immunity, cell adhesion, invasion, cellular proliferation, apoptosis, and angiogenesis (7Viatour P. Merville M.P. Bours V. Chariot A. Phosphorylation of NF-κB and IκB proteins: implications in cancer and inflammation.Trends Biochem Sci. 2005; 30: 43-52Abstract Full Text Full Text PDF PubMed Scopus (1131) Google Scholar). It is activated by diverse pro-inflammatory stimuli (such as IL-1β, TNF-α, lipopolysaccharide, and oxidative stress), which induce expression of multiple genes encoding pro-inflammatory cytokines, chemokines, growth and angiogenic factors, adhesion molecules (e-selectin, ICAM-1, VCAM-1), and inducible enzymes (iNOS, COX-2). To date, only a few in vitro studies have evaluated the involvement of this transcriptional factor in the pathogenesis of endometriosis (8Guo S.W. Nuclear factor-κB (NF-κB): an unsuspected major culprit in the pathogenesis of endometriosis that is still at large?.Gynecol Obstet Invest. 2007; 63: 71-97Crossref PubMed Scopus (123) Google Scholar). In the only existing in vivo experimental model, González Ramos et al. (9González-Ramos R, Van Langendonckt A, Defrère S, Lousse JC, Mettlen M, Donnez J. Agents blocking the nuclear factor-kappa B (NF-κB) pathway are effective inhibitors of endometriosis in an in vivo experimental model. Gynecol Obstet Invest. In press.Google Scholar) tested two NF-κB inhibitors (BAY 11-7085 and SN-50) in nude mice. This study showed that both NF-κB inhibitors can induce a significant reduction in lesion development, and that NF-κB inhibition decreases ICAM-1 expression and cell proliferation but increases apoptosis of endometriotic lesions. To our knowledge, there are no published data on NF-κB activation in human peritoneal macrophages in case of endometriosis. To better understand the mechanisms underlying macrophage inflammatory response and activation in endometriosis, we evaluated the activation of the NF-κB pathway in peritoneal macrophages of patients with endometriosis as compared with controls. Peritoneal fluid samples were collected from 44 patients with (n = 22) and without (n = 22) endometriosis who were undergoing laparoscopy during the proliferative (endometriosis, n = 10; control, n = 9) and secretory (endometriosis, n = 12; control, n = 13) phases of the menstrual cycle. All patients had regular cycles and had received no hormone treatment for at least 3 months before surgery. Control patients (n = 22; mean age, 35.9 ± 7.3 years) undergoing laparoscopy for benign disease showed no endometriotic lesions at laparoscopy. In patients with moderate to severe endometriosis (n = 22; mean age: 33.5 ± 3.8 years), endometriotic lesions were visible at laparoscopy and were later confirmed histologically. Collection of peritoneal fluid samples was approved by the ethics review board of the Catholic University of Louvain. Peritoneal fluid was collected during laparoscopy after insertion of the suction probe through the first counterincision. Care was taken to avoid any contamination of the sample with blood from the abdominal wall. The fluid was aspirated from the cul-de-sac into a sterile syringe and immediately transported on ice to the laboratory. We used a Percoll discontinuous density gradient to isolate the peritoneal macrophages from other cells. Peritoneal fluid was centrifuged at 400 × g for 5 minutes to separate cells and peritoneal fluid supernatant. Peritoneal cells were resuspended in 2 mL of 45% Percoll solution (Amersham Pharmacia Biotech AB, Uppsala, Sweden). Successive density layers were subsequently added to a 15-mL conical tube: 2 mL of 55% Percoll solution, 2 mL of 50% Percoll solution, 2 mL of 45% Percoll solution containing peritoneal cells, 2 mL of 30% Percoll solution, and finally 2 mL of macrophage medium on top (DMEM-F12 containing 10% decomplemented fetal bovine serum (FBS) (GIBCO BRL, Paisley, Renfrewshire, Scotland, U.K.), 100 IU/mL of penicillin, 100 μg/mL of streptomycin, and 0.25 μg/mL of amphotericin B (GIBCO BRL). The gradient tube was centrifuged at 300 × g for 20 minutes. The top two cell fractions, which contained the greatest proportion of macrophages, were fixed in formol and projected onto SuperFrost Plus Slides (Menzel-Gläser, Braunschweig, Germany) by centrifugation (Cytospin Thermo Electron Corporation, Marietta, GA) at 55 × g for 5 minutes. The purity of macrophage isolation was assessed immunohistochemically using mouse monoclonal antibodies to human CD163 (clone RM3/1; Sanbio, Uden, the Netherlands) (1:900 dilution), which is a specific marker for monocytic-macrophage lineage. Immunocytochemical staining for NF-kB was performed on peritoneal macrophages using mouse monoclonal antibody to human NF-κB p65 (F-6) (Tebu-Bio NV, Boechout, Belgium) (1:50 dilution). The cells were then incubated with a secondary antibody conjugated to peroxidase (EnVision+, Dakocytomation, Glostrup, Denmark). Activation of NF-κB was evaluated in each patient by counting NF-κB–positive and NF-κB–negative nuclei of 200 peritoneal macrophages at ×400 magnification. This evaluation was carried out by two blinded independent observers and showed less than 5% variation per sample. Immunostaining of NF-κB p65 was detected in the cytoplasm and nucleus of peritoneal macrophages (Fig. 1A). Nuclear immunostaining was considered as an indicator of NF-κB nuclear translocation. Indeed, activation of the NF-κB pathway requires phosphorylation and degradation of IκB, the natural inhibitor of NF-κB in the cytoplasm, leading to nuclear translocation of activated NF-κB (10Perkins N.D. Integrating cell-signalling pathways with NF-κB and IKK function.Nat Rev Mol Cell Biol. 2007; 8: 49-62Crossref PubMed Scopus (1887) Google Scholar). Proportions of NF-κB–positive nuclei in peritoneal macrophages of patients with and without endometriosis are expressed as medians and interquartile ranges (IQR). Because data were not normally distributed, they were analyzed using the nonparametric two-tailed Mann-Whitney U test (SPSS 14.0). P<.05 was considered statistically significant. The peritoneal macrophages from endometriosis patients showed a statistically significant higher proportion of NF-κB nuclear translocation (positive nuclear cells/total cells) than the peritoneal macrophages from control patients (median: 0.73, IQR: 0.53, 0.86; and median: 0.58, IQR: 0.31, 0.71, respectively; P=.027) (Fig. 1B). No statistically significant differences in macrophage NF-κB activation were found between the endometriosis or control patients according to menstrual cycle phase (data not shown). González Ramos et al. (11González-Ramos R. Donnez J. Defrère S. Leclercq I. Squifflet J. Lousse J.C. et al.Nuclear factor-kappa B (NF-κB) is constitutively activated in peritoneal endometriosis.Mol Hum Reprod. 2007; 13: 503-509Crossref PubMed Scopus (118) Google Scholar) demonstrated constitutive NF-κB activation in human peritoneal endometriotic lesions. The present study provides the first comparison of NF-κB activation in peritoneal macrophages between women with and without endometriosis, demonstrating increased activation of this transcriptional factor in case of endometriosis. Macrophage activation contributes to the pathology of many inflammatory diseases, in which inappropriate regulation of NF-κB activity has been implicated (such as inflammatory bowel disease, rheumatoid arthritis, atherosclerosis, asthma) (12Roman-Blas J.A. Jimenez S.A. NF-κB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis.Osteoarthritis Cartilage. 2006; 14: 839-848Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar, 13Calzado M.A. Bacher S. Schmitz M.L. NF-kappaB inhibitors for the treatment of inflammatory diseases and cancer.Curr Med Chem. 2007; 14: 367-376Crossref PubMed Scopus (126) Google Scholar). In endometriosis, activated peritoneal macrophages are involved in the initiation, maintenance, and progression of peritoneal lesions. Indeed, upon arrival in the peritoneal cavity, endometrial tissue is likely to adhere to the mesothelial lining (14Dunselman G. Groothuis P. de Goeij A. Evers J. The mesothelium, Teflon or Velcro? Mesothelium in endometriosis pathogenesis.Hum Reprod. 2001; 16: 605-607Crossref PubMed Scopus (40) Google Scholar). This adhesion process may be promoted by cell adhesion molecules and soluble factors produced by peritoneal macrophages (15Beliard A. Noël A. Goffin F. Frankenne F. Foidart J.M. Adhesion of endometrial cells labelled with 111Indium-tropolonate to peritoneum: a novel in vitro model to study endometriosis.Fertil Steril. 2003; 79: 724-729Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Endometrial tissue may also adhere if there is too much regurgitated endometrial tissue or if the capacity of intra-abdominal cells to clear the abdominal cavity is impaired (4Dunselman Peritoneal environment in endometriosis.in: Shaw R.W. Endometriosis: current understanding and management. Blackwell Science, Oxford1995: 47-74Google Scholar, 5Vinatier D. Cosson M. Dufour P. Is endometriosis an endometrial disease?.Eur J Obstet Gynecol Reprod Biol. 2000; 91: 113-125Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). After adhesion, endometrial cell invasion requires extracellular matrix breakdown, mainly induced by matrix metalloproteinases (MMPs), which are up-regulated in case of endometriosis (16Kokorine I. Nisolle M. Donnez J. Eeckhout Y. Courtoy P. Marbaix E. Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions.Fertil Steril. 1997; 68: 246-251Abstract Full Text PDF PubMed Scopus (134) Google Scholar, 17Nap A. Groothuis P. Demir A. Evers J. Dunselman G. Pathogenesis of endometriosis.Best Pract Res Clin Obstet Gynaecol. 2004; 18: 233-244Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Some MMPs are produced by peritoneal macrophages, and their activity is mediated by peritoneal inflammatory cytokines and growth factors (17Nap A. Groothuis P. Demir A. Evers J. Dunselman G. Pathogenesis of endometriosis.Best Pract Res Clin Obstet Gynaecol. 2004; 18: 233-244Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). After invasion, endometrial growth and angiogenesis of early endometriotic lesions may also be promoted by steroids and other inflammatory macrophage products. Identification of the transduction pathways involved in macrophage activation in endometriosis may thus offer better targeted therapies in the future. Indeed, inhibition of macrophage activity could probably be very useful for the treatment of endometriosis, as observed in many other inflammatory diseases. Research into the molecules inhibiting the NF-κB pathway in activated macrophages (18Suzuki E. Umezawa K. Inhibition of macrophage activation and phagocytosis by a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin.Biomed Pharmocother. 2006; 60: 578-586Crossref PubMed Scopus (53) Google Scholar, 19Sakaeda Y. Hiroi M. Shimojima T. Iguchi M. Kanegae H. Ohmori Y. Sulindac, a nonsteroidal anti-inflammatory drug, selectively inhibits interferon-γ-induced expression of the chemokine CXCL9 gene in mouse macrophages.Biochem Biophys Res Commun. 2006; 350: 339-344Crossref PubMed Scopus (10) Google Scholar) could well prove to be a major field of investigation in the development of medical therapies for endometriosis. The authors thank the Department of Gynecology for providing peritoneal fluid samples; Jean-François Heilier, Jérémie Gras, and Alain Guillet for their help with statistical analysis; and Mira Hryniuk for reviewing the English grammar and syntax of the manuscript." @default.
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• W2085484171 date "2008-07-01" @default.
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• W2085484171 title "Increased activation of nuclear factor-kappa B (NF-κB) in isolated peritoneal macrophages of patients with endometriosis" @default.
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