Leukocyte Recruitment, Endothelial Cell Adhesion Molecules, and Transcriptional Control: Insights for Drug Discovery

329 Pages·2001·6.73 MB·English

by  Rodger P. McEver (auth.)

LEUKOCYTE RECRUITMENT,
ENDOTHELIAL CELL ADHESION
MOLECULES, AND
TRANSCRIPTIONAL CONTROL
Insights for Drug Discovery
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
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 978-1-4613-5617-2 ISBN 978-1-4615-1565-4 (eBook)
DOI 10.1007/978-1-4615-1565-4
1. Leukocytes. 2. Cell adhesion. 3. Cell adhesion molecules. 4.
Inflammation-Mediators. 5. NF-kappa B (DNA-binding protein) 1. Collins, Tucker.
QP95.L6472000
612.1' 12-dc21
00-048483
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, photo
copying, recording, or otherwise, without the prior written permission of the publisher,
Springer Science+Business Media, LLC.
Printed on acid-free paper.
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. TheSelectinsin Leukocyte Recruitment
Rodger McEver 1
2. Transcriptional Regulationof the E-Selectin Gene
Tucker Collins, Kelly-Ann Sheppard,
Simos Simeonidis, and David Rose 27
3. The Immunoglobulin Superfamily in
Leukocyte Recruitment
Ulrich von Andrian 55
4. Regulation of IntercellularAdhesion Molecule
(ICAM) Gene Expression
Thomas Parks and Mary Gerritsen 109
5. Transcriptional Regulation ofVCAM-l
Andrew Neish,Sarita Aggarwal,
and Tucker Collins 175
6. Activation of Nuclear Factor-ids
Frank Lee, Robert Peters, James Chen,
and Thomas Maniatis 203
7. The Basal Transcriptional Apparatus
Stephen Anderson and Jeffrey Parvin 229
8. Therapeutic Regulation ofLeukocyte Adhesion
Molecule Expression
Mary Gerritsen 263
9. The NF-KB System and Drug Discovery
Anthony Manning 303
Index 323
PRINCIPAL CONTRIBUTORS
Collins,Tucker M.D., Ph.D. McEver, Rodger M.D.
Department of Pathology The University of Oklahoma
Brigham and Women's Hospital Health Sciences Center
221 Longwood Avenue 825 N.E. 13th Street
Boston, MA 02115 Oklahoma City, OK 73104
Tel: [phone] Tel: [phone]
Fax: [phone] Fax: [phone]
[email protected] [email protected]
Gerritsen, Mary Ph.D. Neish,Andrew M.D.
Genentech, Inc. Emory University
Cardiovascular Research Woodruff Memorial Research
Department Building, Room 2337
460 Point San Bruno Blvd. 1639 Pierce Street
So. San Francisco, CA 94080 Atlanta, GA 30322
Tel: [phone] Tel: [phone]
Fax: [phone] Fax: [phone]
[email protected] [email protected]
Lee, Frank M.D., Ph.D. Parks, Thomas Ph.D.
Department of Pathology and Cellegy Pharmaceuticals, Inc.
Lab Medicine 349 Oyster Point Boulevard
University of Pennsylvania Suite 200
School of Medicine South San Francisco, CA 94080
218 John Morgan Building Tel: [phone]
Philadelphia, PA 19104 Fax: [phone]
Tel: [phone] [email protected]
Fax: [phone]
[email protected] Parvin, Jeffrey M.D., Ph.D.
Department of Pathology
Maniatis, Thomas Ph.D. Brigham and Women's Hospital
Harvard University 75 Francis Street
Department of Molecular and Boston, MA 02115
Cellular Biology Tel: [phone]
7 Divinity Avenue Fax: [phone]
Cambridge, MA 02138 [email protected]
Tel: [phone]
Fax: [phone] von Andrian, Ulrich M.D.
The Center for Blood Research
Manning, Anthony Ph.D. Harvard Medical School
Pharmacia Corporation 200 Longwood Avenue
St. Louis, MO Boston, MA 02115
Tel: [phone] Tel: [phone]
Fax: [phone] Fax: [phone]
anthony.m.manning@ [email protected]
stl.monsanto.com http://cbrweb.med.harvard.edul-uval
PREFACE: TRANSCRIPTIONAL CONTROL OF
CELL ADHESION MOLECULES
More than a hundred fifty years ago, Julius Cohnheim made the
first microscopic observations ofsmall 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. The sequence of
1,2
cellular events in thejourney 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
thesite ofthereaction isrestored toitsnormal condition.
EndothelialCell
Leukocyte
Figure 1. Schematic diagram of the cellular events in inflammation, shown here for
neutrophils. (ModifiedfromMcEver,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
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 leukocyte
vessel 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 fortheadhesion molecules havebeen 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 willbe useful inthe treatment ofinflammatory 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
11-16
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
xi
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-KBis included because ofits importance in the cytokine
induced 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-KBsignaling system as a potential target
for drug discovery. Taken together, the components ofthe book provide a
unique description of a crucial step in the adhesion process - the
regulation ofendothelial cell adhesion molecule expression - and suggest
that this step may be an important new area for manipulating the
inflammatory response.
TC
MG
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ACKNOWLEDGMENT
The authors gratefully acknowledge the efforts ofJohn Boucher, the copy
editorand page layout artist for this volume.