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      Specific Recruitment of Antigen-presenting Cells by Chemerin, a Novel Processed Ligand from Human Inflammatory Fluids

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          Abstract

          Dendritic cells (DCs) and macrophages are professional antigen-presenting cells (APCs) that play key roles in both innate and adaptive immunity. ChemR23 is an orphan G protein–coupled receptor related to chemokine receptors, which is expressed specifically in these cell types. Here we present the characterization of chemerin, a novel chemoattractant protein, which acts through ChemR23 and is abundant in a diverse set of human inflammatory fluids. Chemerin is secreted as a precursor of low biological activity, which upon proteolytic cleavage of its COOH-terminal domain, is converted into a potent and highly specific agonist of ChemR23, the chemerin receptor. Activation of chemerin receptor results in intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of p42–p44 MAP kinases, through the G i class of heterotrimeric G proteins. Chemerin is structurally and evolutionary related to the cathelicidin precursors (antibacterial peptides), cystatins (cysteine protease inhibitors), and kininogens. Chemerin was shown to promote calcium mobilization and chemotaxis of immature DCs and macrophages in a ChemR23-dependent manner. Therefore, chemerin appears as a potent chemoattractant protein of a novel class, which requires proteolytic activation and is specific for APCs.

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          Most cited references 23

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          International union of pharmacology. XXII. Nomenclature for chemokine receptors.

          Chemokine receptors comprise a large family of seven transmembrane domain G protein-coupled receptors differentially expressed in diverse cell types. Biological activities have been most clearly defined in leukocytes, where chemokines coordinate development, differentiation, anatomic distribution, trafficking, and effector functions and thereby regulate innate and adaptive immune responses. Pharmacological analysis of chemokine receptors is at an early stage of development. Disease indications have been established in human immunodeficiency virus/acquired immune deficiency syndrome and in Plasmodium vivax malaria, due to exploitation of CCR5 and Duffy, respectively, by the pathogen for cell entry. Additional indications are emerging among inflammatory and immunologically mediated diseases, but selection of targets in this area still remains somewhat speculative. Small molecule antagonists with nanomolar affinity have been reported for 7 of the 18 known chemokine receptors but have not yet been studied in clinical trials. Virally encoded chemokine receptors, as well as chemokine agonists and antagonists, and chemokine scavengers have been identified in medically important poxviruses and herpesviruses, again underscoring the importance of the chemokine system in microbial pathogenesis and possibly identifying specific strategies for modulating chemokine action therapeutically. The purpose of this review is to update current concepts of the biology and pharmacology of the chemokine system, to summarize key information about each chemokine receptor, and to describe a widely accepted receptor nomenclature system, ratified by the International Union of Pharmacology, that is facilitating clear communication in this area.
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            Chemokines in pathology and medicine.

             M Baggiolini (2001)
            About 50 human chemokines and nearly 20 receptors have been identified and characterized in little more than a decade since the discovery of interleukin 8 (IL-8), the first chemotactic cytokine. Research in this field has dramatically changed our understanding of leucocyte traffic in inflammation and immunity. This paper has been written for scientists and practitioners in the field of medicine. It reviews in concise and intelligible form information that I consider useful for understanding the role of chemokines in human pathophysiology. The main areas covered are: (i) the basics of chemokine structures, mode of action, activities and selectivity; (ii) newer aspects of the broad involvement of chemokines in the regulation of immune defence and the housekeeping of the immune system; (iii) the role of chemokines in pathology as illustrated by animal models and studies of human diseases; and (iv) novel therapeutic approaches for a variety of inflammatory conditions, which are based on modulation of chemokine activity.
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              A giant nucleopore protein that binds Ran/TC4.

              Ran/TC4 is a small nuclear G protein that forms a complex with the chromatin-bound guanine nucleotide release factor RCC1 (ref. 2). Loss of RCC1 causes defects in cell cycle progression, RNA export and nuclear protein import. Some of these can be suppressed by overexpression of Ran/TC4 (ref. 1), suggesting that Ran/TC4 functions downstream of RCC1. We have searched for proteins that bind Ran/TC4 by using a two-hybrid screen, and here we report the identification of RanBP2, a novel protein of 3,224 residues. This giant protein comprises an amino-terminal 700-residue leucine-rich region, four RanBP1-homologous (refs 9, 10) domains, eight zinc-finger motifs similar to those of NUP153 (refs 11, 12), and a carboxy terminus with high homology to cyclophilin. The molecule contains the XFXFG pentapeptide motif characteristic of nuclear pore complex (NPC) proteins, and immunolocalization suggests that RanBP2 is a constituent of the NPC. The fact that NLS-mediated nuclear import can be inhibited by an antibody directed against RanBP2 supports a functional role in protein import through the NPC.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                6 October 2003
                : 198
                : 7
                : 977-985
                Affiliations
                [1 ]Institut de Recherche en Biologie Humaine et Moléculaire, B-1070 Brussels, Belgium
                [2 ]Euroscreen s.a., B-6041 Gosselies, Belgium
                [3 ]Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy
                [4 ]Micromass Ltd., Manchester M23 9LZ, United Kingdom
                [5 ]Department of General Pathology, University of Milan, 20123 Milan, Italy
                [6 ]Section of General Pathology and Immunology, University of Brescia, 25123 Brescia, Italy
                Author notes

                Address correspondence to Marc Parmentier, Institut de Recherche en Biologie Humaine et Moléculaire, ULB Campus Erasme, 808 Route de Lennik, Brussels B-1070, Belgium. Phone: 32-2-5554171; Fax: 32-2-5554655; email: mparment@ 123456ulb.ac.be

                Article
                20030382
                10.1084/jem.20030382
                2194212
                14530373
                Copyright © 2003, The Rockefeller University Press
                Categories
                Article

                Medicine

                macrophages, proteolytic processing, orphan receptor, chemotaxis, dendritic cells

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