Table Of ContentXenobiotics
and Inflammation
Edited by
Lawrence B. Schook
Department of Veterinary PathoBiology
University of Minnesota
St. Paul, Minnesota
Debra L. Laskin
Program in Toxicology
Rutgers University
Piscataway, New Jersey
Academic Press
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Library of Congress Cataloging-in-Publication Data
Xenobiotics and inflammation / edited by Lawrence B. Schook, Debra L.
Laskin.
p. cm.
Includes bibliographical references and index.
ISBN 0-12-628930-1
1. Immunotoxicology. 2. Xenobiotics—Immunology.
3. Inflammation-Mediators. 4. Cytokines-Pathophysiology.
5. Growth factors—Pathophysiology. I. Schook, Lawrence B.
II. Laskin, Debra L.
RC582.17.X46 1994
616.07'9-dc20 93-48067
CIP
PRINTED IN THE UNITED STATES OF AMERICA
94 95 96 97 98 99 BC 9 8 7 6 5 4 3 2 1
Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
Susanne Becker (249), Alliance Technologies, Inc., Chapel Hill, North Car
olina 27514
David R. Borcherding (97), Department of Chemistry, Marion Merrell Dow
Research Institute, Marion Merrell Dow, Inc., Kansas City, Missouri
64134
Shawn M. Borcherding (97), Worldwide Medical Affairs, Procter and Gam
ble, Cincinnati, Ohio 45241
Mary E. Brandes (33), Laboratory of Immunology, National Institute of
Dental Research, National Institutes of Health, Bethesda, Maryland 20892
Robert B. Devlin (249), Human Studies Division, Health Effects Research
Laboratory, United States Environmental Protection Agency, Research
Triangle Park, North Carolina 27711
Carl K. Edwards, III (97), Department of Immunology, Marion Merrell
Dow Research Institute, Marion Merrell Dow, Inc., Kansas City, Missouri
64134
Michelle R. Frazier-Jessen (17), Department of Cell Biology, Neurobiology,
and Anatomy, Loyola University, Maywood, Illinois 60153
J. Gauldie (71), Molecular Virology and Immunology Programme, Depart
ment of Pathology, McMaster University, Hamilton, Ontario, Canada
L8N 3Z5
Diane E. Heck (217), Department of Environmental and Community Medi
cine, University of Medicine and Dentistry of New Jersey, Robert Wood
Johnson Medical School, Piscataway, New Jersey 08854
Richard L. Jackson (233), Marion Merrell Dow Research Institute, Cincin
nati, Ohio 45215
Richard J. Kascsak (321), New York State Institute for Basic Research in
Developmental Disabilities, Staten Island, New York 10314
Hillel S. Koren (249), Human Studies Division, Health Effects Research
Laboratory, United States Environmental Protection Agency, Research
Triangle Park, North Carolina 27711
xiii
xiv Contributors
Elizabeth J. Kovacs (17), Department of Cell Biology, Neurobiology, and
Anatomy, Loyola University, Maywood, Illinois 60153
Piotr B. Kozlowski (321), New York State Institute for Basic Research in
Developmental Disabilities, Staten Island, New York 10314
George Ku (233), Marion Merrell Dow Research Institute, Cincinnati, Ohio
45215
Debra L. Laskin (149, 301), Department of Pharmacology and Toxicology,
Rutgers University, Piscataway, New Jersey 08854
Jeffrey D. Laskin (217), Department of Environmental and Community
Medicine, University of Medicine and Dentistry of New Jersey, Robert
Wood Johnson Medical School, Piscataway, New Jersey 08854
David A. Lawrence (193), Department of Pharmacology and Toxicology,
Albany Medical College, Albany, New York 12208
John F. Lockwood (173), Laboratory of Molecular Immunology, Depart
ment of PathoBiology, University of Minnesota, St. Paul, Minnesota
55108
Michael I. Luster (1), National Institute of Environmental Health Sciences,
National Institutes of Health, Research Triangle Park, North Carolina
27709
Laureen MacEachern (149), Department of Pharmacology and Toxicology,
Rutgers University, Piscataway, New Jersey 08854
Michael J. McCabe, Jr. (193), Department of Toxicology, Karolinska Insti-
tutet, Stockholm 104 01, Sweden
Michael J. Myers (173), United States Food and Drug Administration,
Division of Veterinary Medical Research, Beltsville, Maryland 20705
Pierre F. Piguet (283), Departement de Pathologie, Universite de Geneve,
CH 1211 Geneve 4, Switzerland
C. D. Richards (71), Molecular Virology and Immunology Programme,
Department of Pathology, McMaster University, Hamilton, Ontario,
Canada L8N 3Z5
Gary J. Rosenthal (1), National Institute of Environmental Health Sciences,
National Institutes of Health, Research Triangle Park, North Carolina
27709
Lawrence B. Schook (173), Laboratory of Molecular Immunology, Depart
ment of PathoBiology, University of Minnesota, St. Paul, Minnesota
55108
Georgia Schuller-Levis (321), New York State Institute for Basic Research,
Staten Island, New York 10314
Sharon M. Wahl (33), Laboratory of Immunology, National Institute of
Dental Research, National Institutes of Health, Bethesda, Maryland 20892
Alice L. Witsell (173), Laboratory of Molecular Immunology, Department
of Animal Sciences, University of Illinois, Urbana, Illinois 61801
Jun Zhang (97), Department of Immunology, Marion Merrell Dow Research
Institute, Marion Merrell Dow, Inc., Kansas City, Missouri 64134
Foreword
There has been an explosion of interest in inflammation in the past 10
years. The likely causes of this excitement are developments in molecular
biology that have enabled structural identification of cytokines, their func
tions, and the genes that regulate their expression and activities. Concur
rently, there has also been a heightened awareness of xenobiotics and their
ubiquitous presence in the environment, as well as their toxic potential.
This book is particularly timely because it relates developments in both
areas and presents an informative and enlightening discussion of recent
developments.
Inflammation has been defined as a localized protective reaction of tissue
to irritation, injury, or infection that is characterized by pain, redness,
swelling, and sometimes loss of function (American Heritage Dictionary, 3rd
Ed., Houghton Mifflin, 1992). This condition also has been defined as a
pathological process consisting of a dynamic complex of cytological and
histological reactions that occur in blood vessels and tissue in response to an
abnormal stimulation caused by a chemical, biological, or physical agent
(modified from Stedman's Medical Dictionary, 12th Ed., William & Wilkins,
1961). Thus, inflammation has an inherent duality of function: protection
and injury.
The cells that constitute the inflammatory response, and the factors they
secrete, are responsible not only for the injury suffered by various organs
but also for the host protection associated with inflammation.
This book is organized into overviews of the basic elements of inflam
mation (i.e., cytokine structure and function) and of xenobiotic bioactivity,
particularly in relation to the immune system. Inflammation can occur in
any tissue. Chapters in this book deal with accumulation and activity of
inflammatory cells in various organs, including the lung, liver, and skin.
However, the text clearly indicates that inflammatory cell production and
interaction do not necessarily lead to injury.
The feature common to all inflammatory responses is the elaboration of
cytokines. Local and systemic responses are independent of the type of
inflammatory stimulus. Chapter 3 presents an overview of inflammatory
xv
xvi Foreword
cytokines; other chapters discuss particular cytokines, as well as their in
duction and regulation by xenobiotics, in greater detail. The selection of
xenobiotic agents for discussion includes, among others, metals, oxidative
air toxicants, organics, and pesticides.
Inflammation functions to restrict damage to tissue and to neutralize the
toxic agent. The questions of primary interest are: How does inflammation
differ with various irritating xenobiotics? Do cytokine profiles in inflam
mation differ depending on the xenobiotic? A provocative answer to this
question is provided in Chapter 1. Xenobiotics may inhibit transcription of
cytokines in macrophages (corticosteroids) or inhibit early activating
events. It is apparent that the nature of the xenobiotic affects the type of
cytokine produced as well as its regulation. Metals, drugs, organometallics,
and ultraviolet radiation influence the patterns of cytokine production. The
immunosuppressant FK 506 influences early activating events and sup
presses growth-promoting cytokines.
Do tissues differ in their responses to a particular xenobiotic? If so, what is
the molecular basis for the difference in response? What is the role of local
tissue components in the inflammatory response? Are local components
independent of the type of inflammation stimulus? These questions and
many more are addressed in this excellent volume.
Inflammation is a highly regulated process. Several chapters are con
cerned with the regulation of the injurious potential of inflammatory cells
while others deal with the accumulation of inflammatory cells in the various
organs. Injury results from a collection of events that appear to be highly
regulated and that include the nature of the substrate with which the cells
interact, the combination and temporal sequence of stimuli, and the rates of
accumulation and removal of cells. Under the appropriate conditions, the
cells mediate damage largely by liberation of oxygen metabolites, cations,
and proteases. Inhibitors and inactivators of each class of compounds are
present in tissues. The net result is a balance of factors.
Occasionally, the xenobiotic is antigenic, resulting in the recruitment of
lymphocytes. Leukocytes produce protein, lipid, and peptide mediators,
including cytokines. Cytokines can modulate every stage of the inflamma
tory response, from initial recruitment to resolution of injury. Cytokines
that have been recognized and are discussed include the interleukins, tu
mor necrosis factor, interferon, macrophage inflammatory protein, trans
forming growth factor, and colony stimulating factor. The cells that produce
the cytokines include the inflammatory infiltrate as well as resident cells.
Cytokines may be preexisting or newly synthesized. The biochemistry and
biology of cytokines are reviewed in Chapter 3, in conjunction with discus
sion of regulatory elements controlling cytokines and transcription factors.
The overlapping and synergistic roles of cytokines are addressed in Chap
ter 3 as well. Regulation occurs among the complexity of mediators. Cells
control the order in which cytokines are produced. Their production is
Foreword χνϋ
transient even in the presence of a continual stimulus. Regulation may
occur at one or more stages of cytokine production or activity: at transcrip
tion, translation, or release. Cytokine function may require accompanying
cell surface activation or activation of the cytokine following its release from
the cells. Other modes of regulation are possible. Regulation may be by
extracellular proteins that limit the activity of secreted cytokines or by
structures such as cell junctions and matrices.
The chapters on xenobiotic-induced inflammatory responses (Chapters
7-14) appropriately build on the information and knowledge presented in
the first half of the book. Comparisons of pulmonary inflammation and
cytokine induction by ozone, for example, with that induced in the same
organ by bleomycin are particularly enlightening.
With the explosion within the past several years of information related to
cytokines and their production, activity, and regulation, this book is unique
in its focus on xenobiotic-induced inflammation and should be found in
personal libraries of all those interested in xenobiotic toxicity.
Meryl Karol
University of Pittsburgh
Preface
In recent years, it has become evident that inflammatory cytokines not
only are involved in the response of the host to xenobiotics, but also are
associated with xenobiotic-induced changes in immune responsiveness
(immunotoxicity). This newfound knowledge clearly indicates a need for a
book that addresses not only the role of cytokines in inflammation but also
the way in which chemicals that affect different organs activate specific
cytokine cascades. Moreover, the use of this information could lead to novel
strategies for designing drugs to control cytokine induction or biological
activity.
This book is organized to provide the reader with an introduction to
cytokines, xenobiotics, and the inflammatory process, including the in
duction of acute-phase proteins. Examples of specific xenobiotics and their
effects on different organ systems, which clearly demonstrate the need to
improve our understanding of the unique nature of organ-specific inflam
matory responses, are included.
The first chapter, by Rosenthal and Luster, provides an excellent over
view of chemically induced changes in the inflammatory process. The au
thors provide examples of chemicals that affect the lung and skin and the
specific cytokines involved in the response of these tissues. Chapter 2, by
Kovacs and Frazier-Jessen, provides the reader with a general overview of
the cells and mediators involved in both acute and chronic inflammation.
The third chapter is an excellent review of the biochemical and biological
features of inflammatory cytokines. In this chapter, Brandes and Wahl also
provide the reader with an important perspective on the interplay between
cytokine cascades. In the fourth chapter, Richards and Gauldie focus on the
induction of acute-phase proteins and their regulation by the inflammatory
cytokines, interleukin 1 and interleukin 6. This chapter also provides a
discussion of how exposure to xenobiotics such as bleomycin, chloride, and
metals can lead to altered levels of cytokines in various disease states. The
first portion of the book ends with a comprehensive review of a specific
cytokine, tumor necrosis factor, and its role in various pathophysiological
processes. This contribution, by Edwards, Borcherding, Zhang, and Bor-
xix
XX Preface
cherding, provides the reader with a clear understanding of how elevated
levels of tumor necrosis factor, which occur in various disease states, can
contribute to the sequelae associated with sepsis and inflammatory diseases
such as arthritis.
The second portion of the book begins with a review by MacEachern and
Laskin on the potential role of mature bone marrow macrophages and
neutrophils in benzene-induced hematotoxicity. This chapter provides an
in-depth description of how in vivo exposure to benzene modifies bone
marrow phagocyte oxidative metabolism, cytokine production, and the
regulation of bone marrow cell proliferation. Chapter 7, by Schook, Witsell,
Lockwood, and Myers, follows with a review of how the hepatotoxic
chemical dimethylnitrosamine can induce alterations in macrophage func
tioning. According to these authors, elevated production of inflammatory
cytokines in the liver can affect macrophage differentiation from bone mar
row stem cells and subsequent functional responsiveness, including cy
tokine production. McCabe and Lawrence contribute a chapter in which the
effects of metals on Β and Τ cell development are discussed. Thus, exposure
to heavy metals can lead to changes in regulatory circuits controlling host
responses. The chapter by Laskin and Heck addresses the role of keratino-
cytes and inflammatory cells that migrate into the skin in tissue injury
induced by dermal irritants. These authors describe studies that clearly
demonstrate that keratinocytes can acquire macrophage-like activity follow
ing exposure to inflammatory mediators. In the next chapter, Ku and Jack
son speculate on the role cytokines play in the pathogenesis of atherosclero
sis. The following chapter by Koren, Devlin, and Becker, is an excellent
in-depth review that addresses the role that cytokines and inflammatory
mediators play in ozone-induced lung injury. This chapter is followed by
one by Piguet on pulmonary fibrosis induced by bleomycin, silica, and
asbestos. This presentation, which contains many examples of how chronic
exposure to these agents leads to elevated cytokine production associated
with fibrosis, is a much needed discussion of the effects of long-term ele
vated cytokine activity. The chapter by Laskin focuses on the potential role
of nonparenchymal cells in liver injury induced by hepatotoxicants. Data
presented document how the inhibition of macrophage functioning and
mediator production abrogates liver injury. The last chapter (Schuller-
Levis, Kozlowski, and Kascsak) provides the reader with an interesting
hypothesis on the role of various inflammatory cells and mediators in the
pathogenesis and progression of central nervous system injury induced by
viral pathogens.
We hope that the introductory chapters, followed by numerous examples
of specific target organ responses, will give the reader a full appreciation for
the many roles that cytokines play in xenobiotic-induced inflammation. The
editors greatly appreciate the opportunity to work with all the authors on
Preface xxi
this project. Our excitement about the significance of their contributions is
highlighted in the Foreword by Meryl Karol. To each of the contributors, we
extend our gratitude, and to the readers, our hope that they will learn as
much as we have about cytokines and the plethora of roles they play in
xenobiotic-induced tissue injury.
Debra L. Laskin
Lawrence B. Schook
