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      Lipoxin A 4 Prevents the Progression of De Novo and Established Endometriosis in a Mouse Model by Attenuating Prostaglandin E 2 Production and Estrogen Signaling

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          Abstract

          Endometriosis, a leading cause of pelvic pain and infertility, is characterized by ectopic growth of endometrial-like tissue and affects approximately 176 million women worldwide. The pathophysiology involves inflammatory and angiogenic mediators as well as estrogen-mediated signaling and novel, improved therapeutics targeting these pathways are necessary. The aim of this study was to investigate mechanisms leading to the establishment and progression of endometriosis as well as the effect of local treatment with Lipoxin A 4 (LXA 4), an anti-inflammatory and pro-resolving lipid mediator that we have recently characterized as an estrogen receptor agonist. LXA 4 treatment significantly reduced endometriotic lesion size and downregulated the pro-inflammatory cytokines IL-1β and IL-6, as well as the angiogenic factor VEGF. LXA 4 also inhibited COX-2 expression in both endometriotic lesions and peritoneal fluid cells, resulting in attenuated peritoneal fluid Prostaglandin E 2 (PGE 2) levels . Besides its anti-inflammatory effects, LXA 4 differentially regulated the expression and activity of the matrix remodeling enzyme matrix metalloproteinase (MMP)-9 as well as modulating transforming growth factor (TGF)-β isoform expression within endometriotic lesions and in peritoneal fluid cells. We also report for first time that LXA 4 attenuated aromatase expression, estrogen signaling and estrogen-regulated genes implicated in cellular proliferation in a mouse model of disease. These effects were observed both when LXA 4 was administered prior to disease induction and during established disease. Collectively, our findings highlight potential targets for the treatment of endometriosis and suggest a pleotropic effect of LXA 4 on disease progression, by attenuating pro-inflammatory and angiogenic mediators, matrix remodeling enzymes, estrogen metabolism and signaling, as well as downstream proliferative pathways.

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          Most cited references 54

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          The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo.

          Lipoxins (LXs) and aspirin-triggered LX (ATL) are trihydroxytetraene-containing eicosanoids generated from arachidonic acid that are distinct in structure, formation, and function from the many other proinflammatory lipid-derived mediators. These endogenous eicosanoids have now emerged as founding members of the first class of lipid/chemical mediators involved in the resolution of the inflammatory response. Lipoxin A(4) (LXA(4)), ATL, and their metabolic stable analogs elicit cellular responses and regulate leukocyte trafficking in vivo by activating the specific receptor, ALX. ALX was the first receptor cloned and identified as a G protein-coupled receptor (GPCR) for lipoxygenase-derived eicosanoids with demonstrated cell type-specific signaling pathways. ALX at the level of DNA has sequence homology to the N-formylpeptide receptor and as an orphan GPCR was initially referred to as the N-formylpeptide receptor-like 1. Although LXA(4) is the endogenous potent ligand for ALX activation, a number of peptides can also activate this receptor to stimulate calcium mobilization and chemotaxis in vitro. In contrast with LXA(4), the counterparts of many of these peptides in vivo remain to be established. The purpose of this review is to highlight the molecular characterization of the ALX receptor and provide an overview of the ALX-LXA(4) axis responsible for anti-inflammatory and proresolving signals in vivo. The information in this review provides further support for the initial nomenclature proposition for this GPCR as ALX.
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            Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology.

            In response to microenvironmental signals, macrophages undergo different activation, including the "classic" proinflammatory phenotype (also called M1), the "alternative" activation induced by the IL-4/IL-13 trigger, and the related but distinct heterogeneous M2 polarization associated with the anti-inflammatory profile. The latter is induced by several stimuli, including IL-10 and TGF-β. Macrophage-polarized activation has profound effects on immune and inflammatory responses and in tumor biology, but information on the underlying molecular pathways is scarce. In the present study, we report that alternative polarization of macrophages requires the transcription factor c-MYC. In macrophages, IL-4 and different stimuli sustaining M2-like polarization induce c-MYC expression and its translocation to the nucleus. c-MYC controls the induction of a subset (45%) of genes associated with alternative activation. ChIP assays indicate that c-MYC directly regulates some genes associated with alternative activation, including SCARB1, ALOX15, and MRC1, whereas others, including CD209, are indirectly regulated by c-MYC. c-MYC up-regulates the IL-4 signaling mediators signal transducer and activator of transcription-6 and peroxisome proliferator-activated receptorγ, is also expressed in tumor-associated macrophages, and its inhibition blocks the expression of protumoral genes including VEGF, MMP9, HIF-1α, and TGF-β. We conclude that c-MYC is a key player in alternative macrophage activation, and is therefore a potential therapeutic target in pathologies related to these cells, including tumors.
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              Genome-wide association meta-analysis identifies new endometriosis risk loci

              We conducted a genome-wide association (GWA) meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese 1 and European 2 ancestry. We show that rs12700667 on chromosome 7p15.2, previously found in Europeans, replicates in Japanese (P = 3.6 × 10−3), and confirm association of rs7521902 on 1p36.12 near WNT4. In addition, we establish association of rs13394619 in GREB1 on 2p25.1 and identify a novel locus on 12q22 near VEZT (rs10859871). Excluding European cases with minimal or unknown severity, we identified additional novel loci on 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and produced P < 5 × 10−8 in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the European and Japanese GWA cohorts (P = 8.8 × 10−11), indicating that many weakly associated SNPs represent true endometriosis risk loci and risk prediction and future targeted disease therapy may be transferred across these populations.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                24 February 2014
                : 9
                : 2
                Affiliations
                [1 ]Mucosal Immunity Laboratory, Department of Gynecology, Obstetrics and Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
                [2 ]Transplantation Centre and Transplantation Immunopathology Laboratory, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
                National Cancer Center, Japan
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GOC RK DG. Performed the experiments: RK ACC IG RR CP LG JCW. Analyzed the data: RK ACC GOC DG. Wrote the paper: RK GOC DG.

                [¤a]

                Current address: Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

                [¤b]

                Current address: Cancer Research UK, London, United Kingdom

                [¤c]

                Current address: Department of Internal Medicine, Ulm University Hospital, Ulm, Germany

                [¤d]

                Current address: Department of Cell Biology and Morphology, University of Lausanne, Lausanne, Switzerland

                [¤e]

                Current address: Geneva Foundation for Medical Education and Research, Versoix, Switzerland

                Article
                PONE-D-13-31578
                10.1371/journal.pone.0089742
                3933674
                808e6983-8dbf-4134-94c1-376a2d821fe4

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 14
                Funding
                This study was funded by the Swiss National Science Foundation (grant number 310030-120761), as well as grants from the European Society of Clinical Microbiology and Infectious Diseases, the Novartis Foundation for Medical-Biological Research, the Roche Research Foundation and the Department of Gynecology and Obstetrics (GOC). DG is supported by the Swiss National Science Foundation (SCORE 32323B-111370 and 32003B-111371), the Faculty of Biology and Medicine of the University of Lausanne, Fondation Medi-CAL Futur, Fondation Pierre Mercier pour la Science and the Institute of Pathology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and physiology
                Reproductive system
                Computational biology
                Molecular genetics
                Gene expression
                Immunology
                Medicine
                Drugs and devices
                Drug research and development
                Endocrinology
                Obstetrics and gynecology

                Uncategorized

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