DOCSLIB.ORG

CXCR2 Related Chemokine Receptors, CXCR1 and Regulation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
CXCR2 Related Chemokine Receptors, CXCR1 and Regulation Actin Filaments Are Involved in the Regulation of Trafficking of Two Closely Related Chemokine Receptors, CXCR1 and CXCR2 This information is current as of September 23, 2021. Alon Zaslaver, Rotem Feniger-Barish and Adit Ben-Baruch J Immunol 2001; 166:1272-1284; ; doi: 10.4049/jimmunol.166.2.1272 http://www.jimmunol.org/content/166/2/1272 Downloaded from References This article cites 61 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/166/2/1272.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Actin Filaments Are Involved in the Regulation of Trafficking of Two Closely Related Chemokine Receptors, CXCR1 and CXCR2 Alon Zaslaver, Rotem Feniger-Barish, and Adit Ben-Baruch The ligand-induced internalization and recycling of chemokine receptors play a significant role in their regulation. In this study, we analyzed the involvement of actin filaments and of microtubules in the control of ligand-induced internalization and recycling of CXC chemokine receptor (CXCR)1 and CXCR2, two closely related G protein-coupled receptors that mediate ELR-expressing CXC chemokine-induced cellular responses. Nocodazole, a microtubule-disrupting agent, did not affect the IL-8-induced reduction in cell surface expression of CXCR1 and CXCR2, nor did it affect the recycling of these receptors following ligand removal and cell recovery at 37°C. In contrast, cytochalasin D, an actin filament depolymerizing agent, promoted the IL-8-induced reduction Downloaded from in cell surface expression of both CXCR1 and CXCR2. Cytochalasin D significantly inhibited the recycling of both CXCR1 and CXCR2 following IL-8-induced internalization, the inhibition being more pronounced for CXCR2 than for CXCR1. Potent inhibition of recycling was observed also when internalization of CXCR2 was induced by another ELR-expressing CXC chemo- kine, granulocyte chemotactic protein-2. By the use of carboxyl terminus-truncated CXCR1 and CXCR2 it was observed that the carboxyl terminus domains of CXCR1 and CXCR2 were partially involved in the regulation of the actin-mediated process of receptor recycling. The cytochalasin D-mediated inhibition of CXCR2 recycling had a functional relevance because it impaired the http://www.jimmunol.org/ ability of CXCR2-expressing cells to mediate cellular responses. These results suggest that actin filaments, but not microtubules, are involved in the regulation of the intracellular trafficking of CXCR1 and CXCR2, and that actin filaments may be required to enable cellular resensitization following a desensitized refractory period. The Journal of Immunology, 2001, 166: 1272–1284. hemokines are small chemotactic cytokines that mediate which consist of the major cellular infiltrate in the course of acute inflammatory processes, hematopoiesis and angiogene- inflammation. Several investigations demonstrated that neutrophil C sis, and play a crucial role in AIDS pathogenesis (1–4). responses could be regulated and desensitized in processes involv- Chemokine-mediated responses are induced by the activation of ing chemokine receptor internalization (12–14). Chemokine recep- specific G protein-coupled receptors (GPCR),2 which are ex- tor internalization and recycling were also shown to be involved in by guest on September 23, 2021 pressed on target cells (5). In similarity to other members of the the regulation of HIV-1 infectivity, as illustrated by the ability of GPCR superfamily, the ability of chemokine receptors to transmit the RANTES antagonist aminooxypentane-RANTES to induce a intracellular signals may be rapidly attenuated, and is tightly reg- highly potent inhibition of HIV-1 entry to target cells. The ami- ulated by different mechanisms, including receptor phosphoryla- nooxypentane-RANTES-mediated inhibition was demonstrated to tion-dependent G protein-uncoupling and receptor internalization be a direct result of its ability to induce elevated levels of CCR5 (6–9). Agonist-induced internalization of GPCR depletes the internalization, and to prevent its recycling back to the plasma mem- plasma membrane of receptors for the agonist and, therefore, may brane, thereby removing a key element of the fusion complex (15). contribute to the desensitization of the functions mediated through Recent interest in the mechanisms regulating ligand-induced these receptors (6–9). Moreover, if the ligand that induced recep- GPCR internalization has led to observations suggesting that some tor internalization is removed, the receptors may be dephosphory- GPCR undergo endocytosis via clathrin-coated pits, in a process lated, recycled back to the plasma membrane and resensitized upon that involves the binding of arrestins to the receptors (8, 9, 16, 17). a subsequent exposure to the same ligand (9–11). Other factors that are potential regulators of the internalization and Chemokine-induced receptor internalization and recycling were recycling processes of GPCR are yet to be defined. In that regard, shown to play a significant role in the regulation of inflammatory elucidation of the involvement of actin filaments and/or microtu- processes, as indicated for example by studies on neutrophils, bules in ligand-induced GPCR intracellular trafficking is of major importance. The plasma membrane is functionally integrated with the cell “cortex” that consists of actin-based cytoskeleton (18). Department of Cell Research and Immunology, George S. Wise Faculty of Life Sci- Therefore, the trafficking of vesicles at the plasma membrane may ences, Tel-Aviv University, Tel-Aviv, Israel necessitate the active rearrangement of actin filaments, which may Received for publication April 10, 2000. Accepted for publication October 20, 2000. then be followed by actin-assisted vesicle budding and fusion at The costs of publication of this article were defrayed in part by the payment of page the plasma membrane. Moreover, microtubules may also play a charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. direct role in trafficking of receptors, and were shown to facilitate 1 Address correspondence and reprint requests to Dr. Adit Ben-Baruch, Department of transport along the trans-golgi network plasma membrane pathway Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv (19–23). University, Tel-Aviv 69978, Israel. E-mail address: [email protected] Although of potentially major importance for the regulation of 2 Abbreviations used in this paper: GPCR, G protein-coupled receptors; CSB, cell ligand-induced receptor intracellular trafficking, the involvement sorter buffer; CXCR, CXC chemokine receptor; ELRϩ-CXC, ELR-expressing CXC; GCP-2, granulocyte chemotactic protein-2; HEK 293, human embryonal kidney 293; of cytoskeleton elements in GPCR trafficking was very minimally PTx, pertussis toxin; WT, wild-type. studied so far. Of high significance is the fact that the contribution Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 1273 of such elements to the regulation of trafficking of chemokine re- with high affinity (31, 38). Control transfections were performed with the ceptors was not addressed in any manner. In that respect, our study vector (pRc/CMV) alone, and the resulting cells did not specifically bind is focused on the elucidation of the role of cytoskeleton elements IL-8, GCP-2, or Abs specific for human CXCR1 or CXCR2 (29, 31, 38, 39). Parental and stable CXCR1-expressing 300-19 pre B cells (kindly do- in the ligand-induced internalization and recycling processes of nated by Dr. M. Wolf, Theodor Kocher Institute, University of Bern, Bern, CXC chemokine receptor (CXCR)1 and CXCR2, two closely re- Switzerland) were grown in RPMI 1640 medium, supplemented with 10% lated receptors that mediate the migration of neutrophils to inflam- FCS, 100 U/ml penicillin, 100 ␮g/ml streptomycin, 250 ng/ml amphoter- matory sites in response to ELR-expressing CXC (ELRϩ-CXC) icin, 2 mM L-glutamine, 1ϫ non essential amino acids (all purchased from Biological Industries, Beit Haemek, Israel), and 0.05% mM 2-ME (Sigma, chemokines (1, 5, 24). The use of CXCR1 and CXCR2 allowed us Rehovot, Israel). The DNA for CXCR1 transfection was expressed in a to compare between two chemokine receptors that have similar SR-␣-puro vector. Puromycin (1 ␮g/ml; Sigma) was used for selection. No general characteristics, but nevertheless are differentially regulated expression of human CXCR1 or CXCR2 was detected on the parental at multiple levels, including their internalization properties 300-19 cells, as determined by monoclonal mouse anti-CXCR1 or anti- (25–37). CXCR2 Abs (R&D Systems,
Load more

Recommended publications
  • Complete Dissertation
    VU Research Portal Chemokine Receptors CXCR3 and CXCR7 Scholten, D.J. 2012 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Scholten, D. J. (2012). Chemokine Receptors CXCR3 and CXCR7: Allosteric Ligand Binding, Biased Signaling, and Receptor Regulation. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 01. Oct. 2021 Chemokine Receptors CXCR3 and CXCR7: Allosteric Ligand Binding, Biased Signaling, and Receptor Regulation Danny Scholten The work described in this thesis was performed at the Leiden/Amsterdam Center for Drug Research (LACDR), Faculty of Sciences, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081HV Amsterdam, The Netherlands. This research was performed in the framework of the Dutch public-private partnership Top Institute Pharma (TI Pharma) in project “The GPCR Forum (D1-105)”.
    [Show full text]
  • The Role of Selected Chemokines and Their Receptors in the Development of Gliomas
    International Journal of Molecular Sciences Review The Role of Selected Chemokines and Their Receptors in the Development of Gliomas Magdalena Groblewska 1, Ala Litman-Zawadzka 2 and Barbara Mroczko 1,2,* 1 Department of Biochemical Diagnostics, University Hospital in Białystok, 15-269 Białystok, Poland; [email protected] 2 Department of Neurodegeneration Diagnostics, Medical University of Białystok, 15-269 Białystok, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-85-831-8785 Received: 29 April 2020; Accepted: 22 May 2020; Published: 24 May 2020 Abstract: Among heterogeneous primary tumors of the central nervous system (CNS), gliomas are the most frequent type, with glioblastoma multiforme (GBM) characterized with the worst prognosis. In their development, certain chemokine/receptor axes play important roles and promote proliferation, survival, metastasis, and neoangiogenesis. However, little is known about the significance of atypical receptors for chemokines (ACKRs) in these tumors. The objective of the study was to present the role of chemokines and their conventional and atypical receptors in CNS tumors. Therefore, we performed a thorough search for literature concerning our investigation via the PubMed database. We describe biological functions of chemokines/chemokine receptors from various groups and their significance in carcinogenesis, cancer-related inflammation, neo-angiogenesis, tumor growth, and metastasis. Furthermore, we discuss the role of chemokines in glioma development, with particular regard to their function in the transition from low-grade to high-grade tumors and angiogenic switch. We also depict various chemokine/receptor axes, such as CXCL8-CXCR1/2, CXCL12-CXCR4, CXCL16-CXCR6, CX3CL1-CX3CR1, CCL2-CCR2, and CCL5-CCR5 of special importance in gliomas, as well as atypical chemokine receptors ACKR1-4, CCRL2, and PITPMN3.
    [Show full text]
  • Structural Determinants of MIF Functions in CXCR2-Mediated Inflammatory and Atherogenic Leukocyte Recruitment
    Structural determinants of MIF functions in CXCR2-mediated inflammatory and atherogenic leukocyte recruitment Christian Weber*†‡, Sandra Kraemer*§, Maik Drechsler†, Hongqi Lue§, Rory R. Koenen†, Aphrodite Kapurniotu¶, Alma Zernecke†, and Ju¨ rgen Bernhagen‡§ †Institute for Molecular Cardiovascular Research (IMCAR); and §Department of Biochemistry and Molecular Cell Biology, RWTH Aachen University, 52056 Aachen, Germany; and ¶Laboratory of Peptide Biochemistry, Center of Integrated Protein Science Munchen,¨ Technische Universität, D-85350 Munich, Germany Edited by Charles A. Dinarello, University of Colorado Health Sciences Center, Denver, CO, and accepted by the Editorial Board August 15, 2008 (received for review April 25, 2008) We have recently identified the archaic cytokine macrophage ing to CCR5 (i.e., HisRS) and CCR3 (i.e., AsnRS) (9, 10), and migration inhibitory factor (MIF) as a non-canonical ligand of the fragments of TyrRS mediate pro-angiogenic activity by direct CXC chemokine receptors CXCR2 and CXCR4 in inflammatory and binding to CXCR1 through a CXCL8 (also known as interleu- atherogenic cell recruitment. Because its affinity for CXCR2 was kin-8; IL-8)-like N-terminal motif consisting of residues Glu, particularly high, we hypothesized that MIF may feature structural Leu, and Arg (ELR) (11). motives shared by canonical CXCR2 ligands, namely the conserved Macrophage migration inhibitory factor (MIF) is a long- N-terminal Glu-Leu-Arg (ELR) motif. Sequence alignment and struc- known T cell cytokine discovered more than four decades ago tural modeling indeed revealed a pseudo-(E)LR motif (Asp-44-X- that more recently has been recognized to be a key mediator of Arg-11) constituted by non-adjacent residues in neighboring loops innate immunity and pleiotropic inflammatory cytokine.
    [Show full text]
  • The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature
    International Journal of Molecular Sciences Review The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature Jan Korbecki 1 , Klaudyna Kojder 2, Patrycja Kapczuk 1, Patrycja Kupnicka 1 , Barbara Gawro ´nska-Szklarz 3 , Izabela Gutowska 4 , Dariusz Chlubek 1 and Irena Baranowska-Bosiacka 1,* 1 Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powsta´nców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; [email protected] (J.K.); [email protected] (P.K.); [email protected] (P.K.); [email protected] (D.C.) 2 Department of Anaesthesiology and Intensive Care, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-281 Szczecin, Poland; [email protected] 3 Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University in Szczecin, Powsta´nców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; [email protected] 4 Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powsta´nców Wlkp. 72 Av., 70-111 Szczecin, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-914661515 Abstract: Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influ- ence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 Citation: Korbecki, J.; Kojder, K.; Kapczuk, P.; Kupnicka, P.; (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors— Gawro´nska-Szklarz,B.; Gutowska, I.; CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8.
    [Show full text]
  • Gene Expression Profiles in the Rat Streptococcal Cell Wall-Induced
    Available online http://arthritis-research.com/content/7/1/R101 ResearchVol 7 No 1 article Open Access Gene expression profiles in the rat streptococcal cell wall-induced arthritis model identified using microarray analysis Inmaculada Rioja1, Chris L Clayton2, Simon J Graham2, Paul F Life1 and Marion C Dickson1 1Rheumatoid Arthritis Disease Biology Department, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK 2Transcriptome Analysis Department, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK Corresponding author: Inmaculada Rioja, [email protected] Received: 3 Jul 2004 Revisions requested: 16 Sep 2004 Revisions received: 4 Oct 2004 Accepted: 9 Oct 2004 Published: 19 Nov 2004 Arthritis Res Ther 2005, 7:R101-R117 (DOI 10.1186/ar1458)http://arthritis-research.com/content/7/1/R101 © 2004 Rioja et al., licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/ 2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is cited. Abstract Experimental arthritis models are considered valuable tools for P < 0.01), showing specific levels and patterns of gene delineating mechanisms of inflammation and autoimmune expression. The genes exhibiting the highest fold increase in phenomena. Use of microarray-based methods represents a expression on days -13.8, -13, or 3 were involved in chemotaxis, new and challenging approach that allows molecular dissection inflammatory response, cell adhesion and extracellular matrix of complex autoimmune diseases such as arthritis. In order to remodelling. Transcriptome analysis identified 10 upregulated characterize the temporal gene expression profile in joints from genes (Delta > 5), which have not previously been associated the reactivation model of streptococcal cell wall (SCW)-induced with arthritis pathology and are located in genomic regions arthritis in Lewis (LEW/N) rats, total RNA was extracted from associated with autoimmune disease.
    [Show full text]
  • Aging T Cell Chemokine Receptor Expression In
    The Journal of Immunology T Cell Chemokine Receptor Expression in Aging1 Ruran Mo,* Jun Chen,* Yin Han,* Cecelia Bueno-Cannizares,* David E. Misek,† Pascal A. Lescure,† Samir Hanash,† and Raymond L. Yung2* Changes in chemokine receptor expression are important in determining T cell migration and the subsequent immune response. To better understand the contribution of the chemokine system in immune senescence we determined the effect of aging on CD4؉ T cell chemokine receptor function using microarray, RNase protection assays, Western blot, and in vitro chemokine transmi- ,gration assays. Freshly isolated CD4؉ cells from aged (20–22 mo) mice were found to express a higher level of CCR1, 2, 4, 5, 6 and 8 and CXCR2–5, and a lower level of CCR7 and 9 than those from young (3–4 mo) animals. Caloric restriction partially or completely restored the aging effects on CCR1, 7, and 8 and CXCR2, 4, and 5. The aging-associated differences in chemokine receptor expression cannot be adequately explained by the age-associated shift in the naive/memory or Th1/Th2 profile. CD4؉ cells from aged animals have increased chemotactic response to stromal cell-derived factor-1 and macrophage-inflammatory protein- 1␣, suggesting that the observed chemokine receptor changes have important functional consequences. We propose that the aging-associated changes in T cell chemokine receptor expression may contribute to the different clinical outcome in T cell chemokine receptor-dependent diseases in the elderly. The Journal of Immunology, 2003, 170: 895–904. he precise mechanisms linking the aging immune system (6–8). T cell-tropic HIV-1 isolates (X4 strains) preferentially use to diseases in the elderly are poorly understood.
    [Show full text]
  • Identification of an Arg-Leu-Arg Tripeptide That Contributes to The
    www.nature.com/scientificreports OPEN Identifcation of an Arg-Leu-Arg tripeptide that contributes to the binding interface between the Received: 3 October 2017 Accepted: 15 March 2018 cytokine MIF and the chemokine Published: xx xx xxxx receptor CXCR4 Michael Lacy1, Christos Kontos2, Markus Brandhofer1, Kathleen Hille2, Sabine Gröning3, Dzmitry Sinitski1, Priscila Bourilhon1, Eric Rosenberg4, Christine Krammer1, Tharshika Thavayogarajah1, Georgios Pantouris4, Maria Bakou2, Christian Weber5,6,7, Elias Lolis4, Jürgen Bernhagen1,6,8 & Aphrodite Kapurniotu2 MIF is a chemokine-like cytokine that plays a role in the pathogenesis of infammatory and cardiovascular disorders. It binds to the chemokine-receptors CXCR2/CXCR4 to trigger atherogenic leukocyte migration albeit lacking canonical chemokine structures. We recently characterized an N-like- loop and the Pro-2-residue of MIF as critical molecular determinants of the CXCR4/MIF binding-site and identifed allosteric agonism as a mechanism that distinguishes CXCR4-binding to MIF from that to the cognate ligand CXCL12. By using peptide spot-array technology, site-directed mutagenesis, structure- activity-relationships, and molecular docking, we identifed the Arg-Leu-Arg (RLR) sequence-region 87–89 that – in three-dimensional space – ‘extends’ the N-like-loop to control site-1-binding to CXCR4. Contrary to wildtype MIF, mutant R87A-L88A-R89A-MIF fails to bind to the N-terminal of CXCR4 and the contribution of RLR to the MIF/CXCR4-interaction is underpinned by an ablation of MIF/CXCR4- specifc signaling and reduction in CXCR4-dependent chemotactic leukocyte migration of the RLR- mutant of MIF. Alanine-scanning, functional competition by RLR-containing peptides, and molecular docking indicate that the RLR residues directly participate in contacts between MIF and CXCR4 and highlight the importance of charge-interactions at this interface.
    [Show full text]
  • The G-Protein Coupled Receptor CMKLR1/Chemr23: Studies on Gene Regulation, Receptor Ligand Activation, and HIV/SIV Co-Receptor Function
    The G-protein coupled receptor CMKLR1/ChemR23: Studies on gene regulation, receptor ligand activation, and HIV/SIV co-receptor function Mårtensson, Ulrika 2005 Link to publication Citation for published version (APA): Mårtensson, U. (2005). The G-protein coupled receptor CMKLR1/ChemR23: Studies on gene regulation, receptor ligand activation, and HIV/SIV co-receptor function. Elsevier. Total number of authors: 1 General rights Unless other specific re-use rights are stated the following general rights apply: Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Read more about Creative commons licenses: https://creativecommons.org/licenses/ Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 An academic dissertation The G-protein coupled receptor CMKLR1/ChemR23: Studies on gene regulation, receptor ligand activation, and HIV/SIV co-receptor function by Ulrika E. A. Mårtensson Division of Molecular Neurobiology Department of Physiological Sciences Faculty of Medicine Lund University, Sweden With the approval of the Faculty of Medicine, Lund University, to be presented for public examination at the BioMedical Center (BMC), Segerfalksalen, April 2, 2005, at 9.15.
    [Show full text]
  • An Investigation Into Sex-Differences in the Regulation and Function of Toll-Like Receptors in Leukocyte Trafficking in Vivo
    An investigation into sex-differences in the regulation and function of Toll-like receptors in leukocyte trafficking in vivo A thesis submitted for the degree of Doctor of Philosophy University of London By Emma Kay Centre for Microvascular Research William Harvey Research Institute Barts & The London School of Medicine and Dentistry Queen Mary University of London Charterhouse Square London EC1M 6BQ UK 1 Acknowledgements I would first and foremost like to express my utmost thanks to Dr Ramona Scotland for giving me the opportunity to carry out this PhD. I must also express my gratitude to Dr James Whiteford for agreeing to supervise me for the last 18 months, and for his support, encouragement, dedication, and optimism for the project. I must also thank Prof Sussan Nourshargh for acting as my second supervisor and allowing me to undertake this project in the Centre for Microvascular Research, and the British Heart Foundation for the funds to support this work. I wish to thank all the members of Microvascular Research, past and present, for their welcome, support, advice, comments and expertise during the past 3 years. I am also grateful to Dr Guglielmo Rosignoli for all the help during the hundreds of hours spent in the FACS room, Dr Lorena Gomez for her help with the bone marrow work, and Arif Mustafa for his time and assistance in the BSU. I express my thanks to Andrew Leese, with whom I have shared the ‘PhD rollercoaster’ with from the beginning, who has always been there to make me smile, and with whom I hope to stay friends for life.
    [Show full text]
  • Functional Distinction Between CXC Chemokines, Interleukin-8
    0023-6837/02/8201-015$03.00/0 LABORATORY INVESTIGATION Vol. 82, No. 1, p. 15, 2002 Copyright © 2002 by The United States and Canadian Academy of Pathology, Inc. Printed in U.S.A. Functional Distinction between CXC Chemokines, Interleukin-8 (IL-8), and Growth Related Oncogene (GRO)␣ in Neutrophil Infiltration Kazunori Fujiwara, Akihiro Matsukawa, Susumu Ohkawara, Katsumasa Takagi, and Masaru Yoshinaga Departments of Pathology (KF, AM, SO, MY) and Orthopedics (KF, KT), Kumamoto University School of Medicine, Honjo, Kumamoto, Japan SUMMARY: Interleukin-8 (IL-8: CXCL8) and growth related oncogene ␣ (GRO␣: CXCL1) are members of the CXC chemokines. In the present study, we explored the functional distinction between these CXC chemokines in the regulation of neutrophil infiltration. Injection of either rabbit IL-8 or GRO␣ (10 ␮g each) into rabbit knee joints resulted in a massive neutrophil infiltration in the joints. At their peak time point (6 hours), the number of neutrophils induced by IL-8 was more than that induced by GRO␣. Each chemokine induced the other chemokine in the joints. TNF␣ activity was induced in the joints after administration of GRO␣, but not IL-8. Treatment with anti-GRO␣ mAb and/or anti-TNF␣ mAb failed to inhibit IL-8-induced neutrophil infiltration. In contrast, either anti-IL-8 IgG or anti-TNF␣ mAb decreased GRO␣-induced response, and the inhibition was further enhanced by coadministration of these antibodies. Thus, it appears that IL-8 acts directly, whereas GRO␣ acts indirectly, in part, on neutrophil infiltration. The distinct difference in TNF␣ production between IL-8 and GRO␣ was further investigated.
    [Show full text]
  • Roles of Chemokines in Thymopoiesis: Redundancy and Regulation
    266 Cellular & Molecular Immunology Review Roles of Chemokines in Thymopoiesis: Redundancy and Regulation Wenxian Fu1 and Weifeng Chen1, 2 Thymus is the primary lymphoid organ involved in the development of thymocytes. Maturation related events of thymocytes within thymus, especially the widely discussed directional migration of thymocytes, is regulated by chemokines via chemokine receptors mediated signaling pathway. Multiple types of chemokines and chemokine receptors, as components of the network-interaction within thymic microenvironment, are involved in the thymopoiesis. It appears that these chemokines are functionally redundant and such phenomenon may be explained not only by the promiscuous, non-one-to-one matching between ligands-receptors within CXC or CC chemokine subfamily, but also by the various spatio-temporal expression patterns within different cell types and developmental stages. The redundancy and regulation of thymus expressed chemokines and chemokine receptors during thymocyte development are herein discussed. Cellular & Molecular Immunology. 2004;1(4):266-273. Key Words: chemokine, chemokine receptor, redundancy, regulation, thymopoiesis Introduction chemokines are produced within the lymphoid tissues and are involved in homeostatic lymphocyte traffic, comprising The chemokines are a family of small, structurally related the ones participating in thymopoiesis we will discuss here. cytokines, functionally involved in leukocyte activation Indeed, many chemokines may play a dual role, acting in and migration. They are divided into four subfamilies inflammatory process, and as factors triggering the termed the CXC, CC, C and CX3C chemokine, respectively, migration of lymphocytes in central and peripheral immune based on the structural and genetic considerations. The organs, depending on the spatio-temporal expression and CXC family is characterized by an amino acid positioned regulation.
    [Show full text]
  • Inflammatory Chemokines in Atherosclerosis
    cells Review Inflammatory Chemokines in Atherosclerosis Selin Gencer 1,† , Bryce R. Evans 2,†, Emiel P.C. van der Vorst 1,3,4,5,‡ , Yvonne Döring 1,2,3,‡ and Christian Weber 1,3,6,7,*,‡ 1 Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, 80336 Munich, Germany; [email protected] (S.G.); [email protected] (E.P.C.v.d.V.); [email protected] (Y.D.) 2 Department of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; [email protected] (B.R.E.); [email protected] (Y.D.) 3 German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany 4 Interdisciplinary Center for Clinical Research (IZKF), Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany 5 Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands 6 Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands 7 Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany * Correspondence: [email protected] † These authors contributed equally to this manuscript and share first authorship. ‡ These authors contributed equally to this manuscript and share last authorship. Abstract: Atherosclerosis is a long-term, chronic inflammatory disease of the vessel wall leading to the formation of occlusive or rupture-prone lesions in large arteries. Complications of atherosclerosis can become severe and lead to cardiovascular diseases (CVD) with lethal consequences. During the last three decades, chemokines and their receptors earned great attention in the research of atherosclerosis as they play a key role in development and progression of atherosclerotic lesions.
    [Show full text]