LEUKOCYTE RECRUITMENT, ENDOTHELIAL CELL ADHESION MOLECULES, AND TRANSCRIPTIONAL CONTROL Insights for Drug Discovery

Transcription

1 LEUKOCYTE RECRUITMENT, ENDOTHELIAL CELL ADHESION MOLECULES, AND TRANSCRIPTIONAL CONTROL Insights for Drug Discovery

2 LEUKOCYTE RECRUITMENT, ENDOTHELIAL CELL ADHESION MOLECULES, AND TRANSCRIPTIONAL CONTROL lnsights for Drug Discovery edited by Tucker Collins Harvard Medical School SPRINGER SCIENCE+BUSINESS MEDIA, LLC

3 Library of Congress Cataloging-in-Publication Data Leukocyte recruitment, endothelial cell adhesion molecules, and transcriptiona1 control: Insights for drug discovery I edited by Tucker Collins. p.cm. Includes bibliographica1 references and index. ISBN ISBN (ebook) DOI / Leukocytes. 2. Cell adhesion. 3. Cell adhesion molecules. 4. Inflammation-Mediators. 5. NF-kappa B (DNA-binding protein) 1. Collins, Tucker. QP95.L ' 12-dc Copyright 2001 by Springer Science+Business Media New York Originally published by Kluwer Academic Publishers in 2001 Softcover reprint ofthe hardcover Ist edition 2001 AlI rights reserved. N o part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher, Springer Science+Business Media, LLC. Printed on acid-free paper.

4 TABLE OF CONTENTS Leukocyte Recruitment, Endothelial Cell Adhesion Molecules, and Transcriptional Control: Insights for Drug Discovery Preface: Transcriptional Control of Cell Adhesion Molecules Tucker Collins and Mary Gerritsen l. The Selectins in Leukocyte Recruitment Rodger McEver 1 2. Transcriptional Regulation of the E-Selectin Gene Tucker Collins, Kelly-Ann Sheppard, Simos Simeonidis, and David Rose The Immunoglobulin Superfamily in Leukocyte Recruitment Ulrich von Andrian Regulation of Intercellular Adhesion Molecule (ICAM) Gene Expression Thomas Parks and Mary Gerritsen Transcriptional Regulation of VCAM-l Andrew Neish, Sarita Aggarwal, and Tucker Collins Activation of Nuclear Factor-ids Frank Lee, Robert Peters, James Chen, and Thomas Maniatis The Basal Transcriptional Apparatus Stephen Anderson and Jeffrey Parvin Therapeutic Regulation of Leukocyte Adhesion Molecule Expression Mary Gerritsen The NF-KB System and Drug Discovery Anthony Manning 303 Index 323

5 PRINCIPAL CONTRIBUTORS Collins, Tucker M.D., Ph.D. Department of Pathology Brigham and Women's Hospital 221 Longwood Avenue Boston, MA Tel: Fax: Gerritsen, Mary Ph.D. Genentech, Inc. Cardiovascular Research Department 460 Point San Bruno Blvd. So. San Francisco, CA Tel: Fax: Lee, Frank M.D., Ph.D. Department of Pathology and Lab Medicine University of Pennsylvania School of Medicine 218 John Morgan Building Philadelphia, PA Tel: Fax: Maniatis, Thomas Ph.D. Harvard University Department of Molecular and Cellular Biology 7 Divinity Avenue Cambridge, MA Tel: Fax: Manning, Anthony Ph.D. Pharmacia Corporation St. Louis, MO Tel: Fax: anthony.m.manning@ stl.monsanto.com McEver, Rodger M.D. The University of Oklahoma Health Sciences Center 825 N.E. 13th Street Oklahoma City, OK Tel: Fax: rodger-mcever@ouhsc.edu Neish, Andrew M.D. Emory University Woodruff Memorial Research Building, Room Pierce Street Atlanta, GA Tel: Fax: aneish@emory.edu Parks, Thomas Ph.D. Cellegy Pharmaceuticals, Inc. 349 Oyster Point Boulevard Suite 200 South San Francisco, CA Tel: Fax: tparks@cellegy.com Parvin, Jeffrey M.D., Ph.D. Department of Pathology Brigham and Women's Hospital 75 Francis Street Boston, MA Tel: Fax: jparvin@rics.bwh.harvard.edu von Andrian, Ulrich M.D. The Center for Blood Research Harvard Medical School 200 Longwood Avenue Boston, MA Tel: Fax: uva@cbr.med.harvard.edu

6 PREFACE: TRANSCRIPTIONAL CONTROL OF CELL ADHESION MOLECULES More than a hundred fifty years ago, Julius Cohnheim made the first microscopic observations of small blood vessels in transparent tissues, such as the tongue and mesentery of the frog. He was the first to describe the initial changes in blood flow, the subsequent edema caused by increased vascular permeability, and the leukocyte adhesive interactions that characterize the acute inflammatory response. 1,2 The sequence of cellular events in the journey of leukocytes from the lumen of the vessel to the interstitial tissues, called extravasation, can be subdivided into a series of sequential events (Figure 1). In the lumen, marginated leukocytes initially roll, then become activated and adhere firmly to endothelium. This is followed by the transmigration of the leukocytes across the endothelial barrier and the underlying basement membrane. Once in the tissue, the leukocytes migrate toward a chemoattractant stimulus generated by local chemokines or chemoattractant peptides produced by the invading organism. Leukocytes then ingest offending agents, process antigens, kill microbes, and degrade necrotic tissue. In many instances, the inflammatory response succeeds in neutralizing the injurious stimulus and the site of the reaction is restored to its normal condition. Endothelial Cell Leukocyte Figure 1. Schematic diagram of the cellular events in inflammation, shown here for neutrophils. (Modified from McEver, Chapter 1). The localized attachment and sequestration of circulating leukocytes is now recognized as a central aspect of the inflammatory response. Localized attachment suggests that the luminal surface of the endothelium can become locally hyperadhesive, a phenomenon that has been a focus of intense investigation. It is now clear that leukocyte adhesion and transmigration are determined by the recognition and binding

7 x of adhesion molecules on the leukocyte to endothelial surfaces, and that chemical mediators such as cytokines and chemokines can modulate these processes.':" In the past decade, our understanding of the structure and function of the vascular adhesion molecules that contribute to leukocytevessel wall interaction has increased dramatically. The key adhesion receptors belong to three molecular families: the selectins, the immunoglobulin supergene family, and the integrins." '? The selectins, named for the N-terminal lectin domain, consist of E-selectin, which is largely restricted to endothelium; P-selectin, present in endothelium and platelets; and L-selectin, which is displayed by most leukocyte types. The immunoglobulin family is large, but includes several family members that are expressed by endothelial cells, notably intercellular adhesion molecule I (ICAM-I) and vascular cell adhesion molecule-i (VCAM-I). Both of these molecules interact with integrin counter-receptors found on leukocytes. The importance of these molecules in the inflammatory response has been demonstrated by studies in patients with defects in leukocyte function, as well as in transgenic mouse models in which the genes for the adhesion molecules have been disrupted. The induction of endothelial adhesion molecule expression is a key aspect in leukocyte recruitment during an inflammatory response. Some inflammatory mediators, notably cytokines such as tumor necrosis factor-a (TNF-a) and interleukin-i (IL-I), induce the transcription and surface expression of endothelial adhesion molecules. For example, E selectin, which is not present in normal endothelium, is dramatically induced at the transcriptional level by the inflammatory cytokines and mediates the adherence of neutrophils, monocytes, and certain types of lymphocytes by binding to its receptors. The same cytokines also induce the expression of VCAM-I and upregulate levels of ICAM-I, which are present at low levels in normal endothelium. The central premise of this book is that by understanding the mechanisms regulating the expression of a select set of vascular cell adhesion molecules, insights might be obtained that will be useful in the treatment of inflammatory diseases. The transcription factor nuclear factor-xis (NF-KB) has emerged as a dominant theme in the regulation of leukocyte adhesion genes. This transcription factor has been referred to as a "master switch" of the inflammatory response, and most likely plays a central role in the regulation of vascular adhesion molecules during acute inflammatory responses to injury and infection Recent studies have provided a correlation between the presence of activated NF-KB, the expression of Nf-xls-dependent genes, and the presence of disease. Importantly, results from animal models have demonstrated that functional inhibition of

8 NF-KB activation can alter the course of disease. Collectively, these studies suggest that NF-KB inhibition may be a viable therapeutic strategy. In this volume, active investigators have been asked to contribute their perspective on specific aspects of this field, as well as on related areas that may be important in understanding the regulation of expression of these molecules. Included are discussion of the structural and functional aspects of two categories of the adhesion molecules: the selectins and the members of the immunoglobulin supergene family. Following each overview is a more specific review on the regulation of relevant family members : E-selectin, VCAM-l, and ICAM-I, respectively. A chapter on NF-KB is included because of its importance in the cytokineinduced expression of each of these vascular adhesion molecules. Because transcriptional activators like NF-KB must interact with the basal transcription machinery to induce gene expression, an overview of the basal apparatus is also included. This book also provides an overview of anti-inflammatory agents and their effects on leukocyte recruitment, as well as a focused look at the NF-KB signaling system as a potential target for drug discovery. Taken together, the components of the book provide a unique description of a crucial step in the adhesion process - the regulation of endothelial cell adhesion molecule expression - and suggest that this step may be an important new area for manipulating the inflammatory response. xi TC MG

9 REFERENCES 1. Cells, Tissues and Disease : Principles of General Pathology. Edited by Majno G, Joris 1. Blackwell Science, Cambridge, MA, Robbins Pathologic Basis of Disease. Sixth Edition. Cotran RS, Kumar V, Collins T. Editors. W.B. Saunders Company, Philadelphia, PA, Butcher Ee. Leukocyte-endothelial cell recognition: three or more steps to diversity and sensitivity. Cell 1991; 76: Springer TA. Traffic Signals for lymphocyte circulation and migration: the multistep paradigm. Cell 1994; 76: Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 1994; 84: Cellular and Molecular Mechanisms of Inflammation - Vascular Adhesion Molecules. Edited by Cochrane CG, Gimbrone, MA. Academic Press Inc., London, Adhesion. Its role in inflammatory disease. Edited by Harlan JM, and Liu DY. W.H. Freeman and Company, New York, The Adhesion Molecule Facts Book. Edited by Pigott R, Power e. Academic Press, London, Frenette PS, Wagner DD. Adhesion molecules. N Engl J Med 1996; 334: Vestweber D, Blanks JE. Mechanisms that regulate the function of the selectins and their ligands. Physiol Rev 1999; 79: Ghosh S, May MJ, Kopp EB. NF-KB and Rei proteins: evolutionarily conserved mediators of immune responses. Ann Rev Immunol 1998; 16: Baldwin AS. The NF-KB and IKB proteins: new discoveries and insights. Ann Rev Immunol 1996; 14: Verma 1M. RelINF-KBIIKB family: intimate tales of association and dissociation. Genes Dev 1995; 9: Baeuerle PA, Baltimore D. NF-KB: ten years after. Cell 1996; 87: Barnes PJ, Karin M. Nuclear factor-xll- a pivotal transcription factor in chronic inflammatory diseases. N. Eng\. J. Med. 1997; 336: Mercurio F, Manning AM. Multiple signals converging on NF-KB. CUff Opin Cell BioI 1999; 11:

10 ACKNOWLEDGMENT The authors gratefully acknowledge the efforts of John Boucher, the copy editor and page layout artist for this volume.