ADENOSINE RECEPTORS Therapeutic Aspects for Inflammatory and Immune Diseases © 2007 by Taylor & Francis Group, LLC CRC is an imprint of the Taylor & Francis Group, an informa business Boca Raton London New York ADENOSINE RECEPTORS Therapeutic Aspects for Inflammatory and Immune Diseases Edited by György Haskó Bruce N. Cronstein Csaba Szabó © 2007 by Taylor & Francis Group, LLC CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2007 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-3999-5 (Hardcover) International Standard Book Number-13: 978-0-8493-3999-8 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the conse- quences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www. copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Adenosine receptors : therapeutic aspects for inflammatory and immune diseases / edited by Gyorgy Hasco, Bruce N. Cronstein, Csaba Szabo. p. cm. Includes bibligraphical references and index. ISBN 0-8493-3999-5 (alk. paper) 1. Adenosine--Receptors. 2. Adenosine--Physiological effect. I. Hasko, Gyorgy. II. Cronstein, Bruce N. III. Szabó, Csaba, M.D. QP625.A27A343 2006 615’.7--dc22 2006041793 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com T&F_LOC_A_Master.indd 1 6/13/06 3:23:49 PM © 2007 by Taylor & Francis Group, LLC Preface ADENOSINE: 100 YEARS OLD AND GOING STRONG! The purine nucleoside adenosine is a modulatory substance that has been intensively studied for about a century by investigators from different biomedical areas because of the plethora of its actions on organs and tissues. Several lines of evidence now indicate that the ability of adenosine to control inflammatory cells plays a key role in the modulatory effects of adenosine in both health and disease. Adenosine indeed has a major impact on the functions of the inflammatory and immune systems. There are many promising emerging therapeutic approaches that focus on the modulation of adenosine, including compounds that interfere with the breakdown of adenosine, as well as specific agonists and antagonists of various adenosine subtypes. Some of these compounds are in intense preclinical investigations, whereas others have already entered clinical trials. In recent years it also became apparent that adenosine is responsible for the anti-inflammatory effect of some compounds that are in therapeutic use, including the antirheumatic disease-modifying agent methotrexate. This recent interest and emerging widespread awareness of the effect of adenosine in the control of the inflammatory and immune systems covers some of the most active areas of biomedical research (heart, vessels, lung, intestine, kidney, skin, and brain). It is expected that this basic knowledge will generate new therapeutic modalities in the very near future for pathologies with large incidence and of major socioeco- nomic impact such as ischemia and reperfusion (vascular injury and transplants), atrial fibrillation, heart disease, wound healing, tumors, atherosclerosis, pain, and a variety of central nervous system diseases (Parkinson’s and Alzheimer’s diseases, epilepsy, mood disorders, and sleep disorders). The data on the role of adenosine in inflammatory and immune responses are being published in a large number of generalist and specialist scientific journals and have not yet been compiled comprehensively into a single publication. This book contains a compilation of reviews on how adenosine, acting at its cellular receptors, regulates immune responses. The book provides the reader with a general overview of adenosine receptors, covering aspects of molecular biology, cell biology, and pharmacology. Separate chapters focus on the role of adenosine receptors in regu- lating the function of the various cell types that are involved in immune responses. Further chapters delineate the role of purinergic signaling in the pathophysiology of a variety of disease states that are associated with an overzealous or insufficient immune response. These include autoimmune diseases, asthma, atherosclerosis, ischemia-reperfusion injury, and cancer. The current book is intended to serve as a useful starting point for investigators entering the field of adenosine and inflamma- tory disease, and also as a handy reference for those already active in the field. 3999_C000.fm Page v Wednesday, May 24, 2006 4:53 PM © 2007 by Taylor & Francis Group, LLC Contributors Sara Bar-Yehuda Can-Fite BioPharma Ltd. and Felsenstein Medical Research Center Tel-Aviv University Petach-Tikva, Israel Italo Biaggioni, M.D. Department of Medicine Vanderbilt, University Nashville, Tennessee Michael R. Blackburn, Ph.D. Department of Biochemistry and Molecular Biology University of Texas–Houston Medical School Houston, Texas Jonathan Blay, Ph.D. Department of Pharmacology Dalhousie University Halifax, Nova Scotia Canada Lara Buscemi Department of Pharmacology University of North Dakota Grand Forks, North Dakota Sean P. Colgan Department of Anesthesiology, Perioperative, and Pain Medicine Brigham and Women’s Hospital Boston, Massachusetts Bruce Cronstein, M.D. Department of Medicine, Pathology, and Pharmacology New York University School of Medicine New York, New York Elisabetta Daré Department of Physiology and Pharmacology Karolinska Institutet Stockholm, Sweden Katrin Färber Cellular Neurosciences Max-Delbruck Centre Berlin, Germany Igor Feoktistov, M.D., Ph.D. Department of Medicine Vanderbilt University Nashville, Tennessee Pnina Fishman Can-Fite BioPharma Ltd. and Felsenstein Medical Research Center Tel-Aviv University Petach-Tikva, Israel Gary S. Firestein, M.D. School of Medicine University of California–San Diego La Jolla, California Julie A. Fotheringham Neuroimmunology Branch National Institute of Neurological Disorders and Stroke Bethesda, Maryland Bertil B. Fredholm, M.D. Department of Physiology and Pharmacology Karolinska Institutet Stockholm, Sweden 3999_C000.fm Page vii Wednesday, June 21, 2006 8:26 AM © 2007 by Taylor & Francis Group, LLC Zhan-Guo Gao National Institute of Diabetes, Digestive, and Kidney Diseases National Institutes of Health Bethesda, Maryland Pallavi Garg Division of Digestive Diseases Emory University School of Medicine Atlanta, Georgia Jonathan D. Geiger, M.D. Department of Pharmacology University of North Dakota Grand Forks, North Dakota Domokos Gerô Department of Human Physiology and Clinical Experimental Research Semmelweis University Medical School Budapest, Hungary Giampiero Girolomoni, M.D. Department of Dermatology University of Jena Jena, Germany György Haskó, M.D., Ph.D. Department of Surgery UMDNJ–New Jersey Medical School Newark, New Jersey David W. Hoskin, Ph.D. Departments of Microbiology and Immunology, and Pathology Dalhousie University Halifax, Nova Scotia Canada Marco Idzko, M.D. Department of Dermatology University of Jena Jena, Germany Kenneth A. Jacobson, Ph.D. National Institute of Diabetes, Digestive, and Kidney Diseases National Institutes of Health Bethesda, Maryland Bhalchandra V. Joshi National Institute of Diabetes, Digestive, and Kidney Diseases National Institutes of Health Bethesda, Maryland Yong Chul Kim Department of Life Science Kwangju Institute of Science and Technology Kwangju, Republic of Korea Karl-Norbert Klotz Institut fur Pharmakologie und Toxikologie Universität Würzburg Würzburg, Germany Vasantha Kolachala Division of Digestive Diseases Emory University School of Medicine Atlanta, Georgia Courtney M. Lappas Department of Pharmacology University of Virginia Charlottesville, Virginia Samuel Joseph Leibovich, Ph.D. Department of Cell Biology and Molecular Medicine UMDNJ–New Jersey Medical School Newark, New Jersey Joel Linden, Ph.D. Department of Internal Medicine University of Virginia Charlottesville, Virginia 3999_C000.fm Page viii Wednesday, June 21, 2006 8:26 AM © 2007 by Taylor & Francis Group, LLC Lea Madi Can-Fite BioPharma Ltd. Petach-Tikva, Israel Edward Martin Department of Internal Medicine University of Virginia Richmond, Virginia Christopher Moore Department of Internal Medicine University of Virginia Richmond, Virginia Johannes Norgauer, M.D., Ph.D. Department of Dermatology University of Jena Jena, Germany Elisabeth Panther, M.D. Department of Dermatology University of Jena Jena, Germany Marc Pouliot, Ph.D. Department of Anatomy-Physiology Laval University Sainte-Foy, Quebec Canada Allison B. Reiss, M.D. Department of Medicine Winthrop University Hospital Mineola, New York Sanna Rosengren, Ph.D. School of Medicine University of California–San Diego La Jolla, California W. Michael Scheld, M.D. Department of Internal Medicine University of Virginia Charlottesville, Virginia Gunnar Schulte Department of Physiology and Pharmacology Karolinska Institutet Stockholm, Sweden Aneesh Sheth Department of Medicine, Pathology, and Pharmacology New York University School of Medicine New York, New York Shanthi V. Sitaraman, M.D., Ph.D. Department of Medicine Emory University Atlanta, Georgia Gail Sullivan Department of Internal Medicine University of Virginia Charlottesville, Virginia Csaba Szabó, M.D., Ph.D. Inotek Pharmaceuticals Beverly, Massachusetts Masahide Takedachi Immunobiology and Cancer Program Oklahoma Medical Research Foundation Oklahoma City, Oklahoma Linda F. Thompson, Ph.D. Immunobiology and Cancer Program Oklahoma Medical Research Foundation Oklahoma City, Oklahoma Mirjana Ziemer, M.D. Department of Dermatology University of Jena Jena, Germany 3999_C000.fm Page ix Wednesday, June 21, 2006 8:27 AM © 2007 by Taylor & Francis Group, LLC Table of Contents Chapter 1 Adenosine Receptor Pharmacology.....................................................1 Karl-Norbert Klotz Chapter 2 Medicinal Chemistry of Adenosine A3 Receptors.............................15 Kenneth A. Jacobson, Yong Chul Kim, Bhalchandra V. Joshi, and Zhan-Guo Gao Chapter 3 The Role of CD73 in the Generation of Extracellular Adenosine for Adenosine Receptor Signaling ..................................39 Masahide Takedachi, Sean P. Colgan, and Linda F. Thompson Chapter 4 Regulation of Monocyte/Macrophage Function by Adenosine Receptors.....................................................................49 György Haskó and Csaba Szabó Chapter 5 Impaired Lymphocyte Activation in the Presence of Adenosine: Mechanisms and Physiologic Relevance...........................................69 Jonathan Blay and David W. Hoskin Chapter 6 Adenosine and Neutrophil Functions ................................................89 Marc Pouliot Chapter 7 Dendritic Cells Regulated by Nucleotides and Nucleosides ..........101 Johannes Norgauer, Marco Idzko, Elisabeth Panther, Giampiero Girolomoni, and Mirjana Ziemer Chapter 8 Adenosine and Endothelial Cell Function.......................................109 Igor Feoktistov and Italo Biaggioni Chapter 9 Adenosine A2B Receptor in the Intestinal Epithelia ........................131 Shanthi V. Sitaraman, Vasantha Kolachala, and Pallavi Garg Chapter 10 Adenosine, Adenosine Receptors, and the Regulation of Glial Cells in Neuronal Damage.................................................145 Gunnar Schulte, Elisabetta Daré, Katrin Färber, and Bertil B. Fredholm 3999_C000.fm Page x Wednesday, May 24, 2006 4:53 PM © 2007 by Taylor & Francis Group, LLC Chapter 11 Adenosine Receptors, Wound Healing, and Angiogenesis .............157 Aneesh Sheth and Bruce Cronstein Chapter 12 A2A Adenosine Receptors and Ischemia Reperfusion Injury..........165 Courtney M. Lappas and Joel Linden Chapter 13 Adenosine Signaling in Chronic Lung Disease ..............................187 Michael R. Blackburn Chapter 14 Role of Adenosine in the Control of Inflammatory Events Associated with Acute and Chronic Neurodegenerative Disorders...........................................................213 Jonathan D. Geiger, Lara Buscemi, and Julie A. Fotheringham Chapter 15 Anti-Inflammatory and Cytoprotective Effects of Inosine..............237 Csaba Szabó, Domokos Gerô, and György Haskó Chapter 16 Adenosine and Infection..................................................................257 Christopher Moore, Edward Martin, Gail Sullivan, Joel Linden, and W. Michael Scheld Chapter 17 Regulation of Peripheral Inflammation by Spinal Adenosine ........285 Sanna Rosengren and Gary S. Firestein Chapter 18 Adenosine, Tumors, and Immunity .................................................299 Pnina Fishman, Sara Bar-Yehuda, and Lea Madi Chapter 19 Adenosine in Atherosclerosis...........................................................313 Allison B. Reiss Chapter 20 Regulation of Macrophage-Dependent Angiogenesis by Adenosine and Toll-Like Receptors ...........................................325 Samuel Joseph Leibovich 3999_C000.fm Page xi Wednesday, May 24, 2006 4:53 PM © 2007 by Taylor & Francis Group, LLC 1 1 Adenosine Receptor Pharmacology Karl-Norbert Klotz CONTENTS 1.1 Introduction ......................................................................................................1 1.2 Adenosine Receptor Subtypes .........................................................................2 1.2.1 Signaling...............................................................................................2 1.2.2 Structure ...............................................................................................3 1.3 Adenosine Receptor Ligands...........................................................................4 1.3.1 Agonists................................................................................................4 1.3.2 Antagonists...........................................................................................7 1.4 Physiological Functions of Adenosine ............................................................9 1.4.1 Cardiovascular Actions ........................................................................9 1.4.2 Adenosine and the Kidney...................................................................9 1.4.3 CNS Actions of Adenosine..................................................................9 1.4.4 Adenosine Receptors and Cancer......................................................10 1.5 Conclusion......................................................................................................10 References................................................................................................................10 1.1 INTRODUCTION Adenosine is a building block of RNA and many small biomolecules such as ATP and NADH, and at the same time it serves as a regulator of tissue function in practically every cell of the human body. The main source of adenosine is from degradation of adenine nucleotides 1,2 and, therefore, its regulatory functions are intricately linked to the energy balance of organs with a high energy demand. A large family of purinergic receptors may respond to ATP, ADP, and adenosine, and thereby orchestrate the respective metabolic requirements of a cell (Figure 1.1). The first documented physiological function of adenosine was the inhibition of AV conduction in mammalian heart and was discovered almost 80 yr ago. 3 This and all other known effects of adenosine are mediated via four subtypes of G-protein- coupled receptors named A 1 , A 2A , A 2B , and A 3 (for a recent review see Reference 4). Adenosine receptors are also classified as P1 receptors in order to distinguish them from the large P2 subfamily of purinergic receptors specific for ATP, ADP, and other nucleotides. 5,6 Adenosine plays the most important regulatory roles in the cardiovas- cular system, kidney, and CNS, which are briefly discussed in this introductory chapter. 3999_C001.fm Page 1 Tuesday, May 23, 2006 4:47 PM © 2007 by Taylor & Francis Group, LLC