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      Regulation of CCL2 Expression by an Upstream TALE Homeodomain Protein-Binding Site That Synergizes with the Site Created by the A-2578G SNP

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          Abstract

          CC Chemokine Ligand 2 (CCL2) is a potent chemoattractant produced by macrophages and activated astrocytes during periods of inflammation within the central nervous system. Increased CCL2 expression is correlated with disease progression and severity, as observed in pulmonary tuberculosis, HCV-related liver disease, and HIV-associated dementia. The CCL2 distal promoter contains an A/G polymorphism at position -2578 and the homozygous -2578 G/G genotype is associated with increased CCL2 production and inflammation. However, the mechanisms that contribute to the phenotypic differences in CCL2 expression are poorly understood. We previously demonstrated that the -2578 G polymorphism creates a TALE homeodomain protein binding site (TALE binding site) for PREP1/PBX2 transcription factors. In this study, we identified the presence of an additional TALE binding site 22 bp upstream of the site created by the -2578 G polymorphism and demonstrated the synergistic effects of the two sites on the activation of the CCL2 promoter. Using chromatin immunoprecipitation (ChIP) assays, we demonstrated increased binding of the TALE proteins PREP1 and PBX2 to the -2578 G allele, and binding of IRF1 to both the A and G alleles. The presence of TALE binding sites that form inverted repeats within the -2578 G allele results in increased transcriptional activation of the CCL2 distal promoter while the presence of only the upstream TALE binding site within the -2578 A allele exerts repression of promoter activity.

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          Most cited references45

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          MCP-1: chemoattractant with a role beyond immunity: a review.

          Monocyte Chemoattractant Protein (MCP)-1, a potent monocyte attractant, is a member of the CC chemokine subfamily. MCP-1 exerts its effects through binding to G-protein-coupled receptors on the surface of leukocytes targeted for activation and migration. Role of MCP-1 and its receptor CCR2 in monocyte recruitment during infection or under other inflammatory conditions is well known. A comprehensive literature search was conducted from the websites of the National Library of Medicine (http://www.ncbl.nlm.nih.gov) and Pubmed Central, the US National Library of Medicine's digital archive of life sciences literature (http://www.pubmedcentral.nih.gov/). The data was assessed from books and journals that published relevant articles in this field. Recent and ongoing research indicates the role of MCP-1 in various allergic conditions, immunodeficiency diseases, bone remodelling, and permeability of blood - brain barrier, atherosclerosis, nephropathies and tumors. MCP-1 plays an important role in pathogenesis of various disease states and hence MCP-1 inhibition may have beneficial effects in such conditions. 2010 Elsevier B.V. All rights reserved.
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            Chemokines in the pathogenesis of vascular disease.

            Our increasing appreciation of the importance of inflammation in vascular disease has focused attention on the molecules that direct the migration of leukocytes from the blood stream to the vessel wall. In this review, we summarize roles of the chemokines, a family of small secreted proteins that selectively recruit monocytes, neutrophils, and lymphocytes to sites of vascular injury, inflammation, and developing atherosclerosis. Chemokines induce chemotaxis through the activation of G-protein-coupled receptors, and the receptors that a given leukocyte expresses determines the chemokines to which it will respond. Monocyte chemoattractant protein 1 (MCP-1), acting through its receptor CCR2, appears to play an early and important role in the recruitment of monocytes to atherosclerotic lesions and in the formation of intimal hyperplasia after arterial injury. Acute thrombosis is an often fatal complication of atherosclerotic plaque rupture, and recent evidence suggests that MCP-1 contributes to thrombin generation and thrombus formation by generating tissue factor. Because of their critical roles in monocyte recruitment in vascular and nonvascular diseases, MCP-1 and CCR2 have become important therapeutic targets, and efforts are underway to develop potent and specific antagonists of these and related chemokines.
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              A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression.

              Two novel polymorphisms in the distal regulatory region of the MCP-1 gene were identified by directly sequencing PCR amplified genomic DNA. These polymorphisms are located at positions -2518 (G or A) and -2076 (A or T) relative to the major transcriptional start site of the gene. To examine the effect of these polymorphisms on MCP-1 transcription, polymorphic variants of the MCP-1 distal regulatory region were placed upstream of a luciferase reporter gene and transfected into A172 cells. IL-1beta-induced luciferase activity was significantly greater from cells transfected with constructs containing G at position -2518. The polymorphism at -2076 did not affect MCP-1 transcription. IL-1beta-treated peripheral blood mononuclear cells from individuals heterozygous or homozygous for G at -2518 produced more MCP-1 than cells from individuals homozygous for A at -2518. These data identify a polymorphism in the MCP-1 distal regulatory region that affects the level of MCP-1 expression in response to an inflammatory stimulus. Copyright 1999 Academic Press.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                8 July 2011
                : 6
                : 7
                : e22052
                Affiliations
                [1 ]McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [2 ]Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [3 ]Department of Neurology, Pathology and Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [4 ]The Henry M. Jackson Foundation for the Advancement of Military Medicine, Washington, D. C., United States of America
                Fundació Institut Germans Trias i Pujol; Universitat Autònoma de Barcelona CibeRES, Spain
                Author notes

                Conceived and designed the experiments: SHP EKW LG JEC. Performed the experiments: SHP. Analyzed the data: SHP JEC. Contributed reagents/materials/analysis tools: JEC. Wrote the paper: SHP EKW LG JEC.

                Article
                PONE-D-11-02682
                10.1371/journal.pone.0022052
                3132772
                21760952
                4bcf6a67-0177-459a-b29c-d29e389a0b8b
                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
                History
                : 7 February 2011
                : 15 June 2011
                Page count
                Pages: 8
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Neurological System
                Central Nervous System
                Genetics
                Gene Expression
                DNA transcription
                Immunology
                Immunity
                Inflammation
                Immunologic Subspecialties
                Pulmonary Immunology
                Genetics of the Immune System
                Microbiology
                Immunity
                Inflammation
                Molecular Cell Biology
                Gene Expression
                Neuroscience
                Neurophysiology
                Central Nervous System
                Medicine
                Anatomy and Physiology
                Neurological System
                Central Nervous System
                Clinical Immunology
                Immunity
                Inflammation
                Infectious Diseases
                Bacterial Diseases
                Tuberculosis
                Tropical Diseases (Non-Neglected)
                Tuberculosis

                Uncategorized
                Uncategorized

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