Table Of ContentJOHN JACOB ABEL SYMPOSIA
ON DRUG DEVELOPMENT
J. Thomas August, Series Editor
Biological Response Mediators and Modulators, J. Thomas August, editor
1983
Biological Response
Mediators
and Modulators
EDITED BY
J. Thomas August
Department of Pharmacology and
Experimental Therapeutics
The Johns Hopkins University
Baltimore, Maryland
ACADEMIC PRESS
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Academic Press Rapid Manuscript Reproduction
Proceedings of the Second John Jacob Abel Symposium on Drug
Development Held at The Johns Hopkins University School of Medicine,
Baltimore, Maryland, on June 21-23, 1982
COPYRIGHT© 1983, BY ACADEMIC PRESS, INC.
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Library of Congress Cataloging in Publication Data
Main entry under title:
Biological response mediators and modulators.
Proceedings of the 2nd John Jacob Abel Symposium on
Drug Development, held June 21-23, 1982, at the Johns
Hopkins University School of Medicine, Baltimore, Md.
Includes index.
1. Metabolism-Regulation-Congresses. 2. Cell
receptors-Congresses. 3. Cell metabolism-Congresses.
4. Pharmacology, Experimental-Congresses. I. August,
J.Thomas. II. John Jacob Abel Symposium on Drug Develop
ment (2nd : 1982 : Johns Hopkins University School of
Medicine) [DNLM: 1. Receptors, Endogenous substances-
Metabolism-Congresses. 2. Endocytosis-Drug effects-
Congresses. 3. Arachidonic acids-Metabolism-Congresses.
4. Macrophage activation-Drug effects-Congresses.
5. Cells-Drug effects-Congresses. W3 J012J 2nd
1982b /QV38B6155 1982]
QP171.B6937 1983 615'.7 83-19729
ISBN 0-12-068050-5
PRINTED IN THE UNITED STATES OF AMERICA
83 84 85 86 9 8 7 6 5 4 3 2 1
John Jacob Abel was the founder of academic pharmacology in the
United States and established the Department of Pharmacology at
the newly formed School of Medicine of The Johns Hopkins Uni
versity in 1893. The name of the new department was significant:
' * Materia medica' ' previously designated only studies of the clinical
efficacy of available drugs. "Pharmacology" encompassed the ex
perimental study of basic biochemical and physiological interactions
of cells and organ systems with natural and foreign substances.
The basis of Abel's program throughout was a vigorous effort in
fundamental research. "It was experiments of this type—born from
the interaction of chemistry, physics, and physiology—that demon
strated ... and buttressed the view that pharmacology must encom
pass and exploit basic science ..." These efforts led Abel to found
the Journal of Biological Chemistry in 1905 (with Dr. Christian
Herter), and the Journal of Pharmacology and Experimental
Therapeutics in 1909.
This symposium is dedicated to the memory of John Jacob Abel.
Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
G. Kenneth Adams III (83), The Johns Hopkins University School of Medicine, The
Good Samaritan Hospital, Baltimore, Maryland 21239
Sucharit Bhakdi (141), Institute of Medical Microbiology, Schubertstr. 1, D-6300
dessen, West Germany
Michael S. Brown (1), Departments of Molecular Genetics and Internal Medicine,
University of Texas Health Science Center at Dallas, Dallas, Texas 75235
Stanley Cohen (7), Department of Biochemistry, Vanderbilt University School of
Medicine, Nashville, Tennessee 37232
A.W. Ford-Hutchinson (59), Merck Frosst Canada, Inc., Pointe Claire, Dorval,
Quebec, Canada H9R 4P8
Robert M. Friedman (199), Department of Pathology, Uniformed Services Univer
sity of the Health Sciences, Bethesda, Maryland 20814
Steven Gillis (177), Program in Basic Immunology, Fred Hutchinson Cancer Re
search Center, Seattle, Washington 98104
Joseph L. Goldstein (1), Departments of Molecular Genetics and Internal Medicine,
University of Texas Health Science Center at Dallas, 5323 Harry Hines Boulevard,
Dallas, Texas 75235
Marilyn Halonen (67), Division of Respiratory Sciences, University of Arizona Col
lege of Medicine, Tucson, Arizona 85724
Donald J. Hanahan (67), Department of Biochemistry, University of Texas Health
Science Center at San Antonio, San Antonio, Texas 78284
Christophers. Henney (177), Program in Basic Immunology, Fred Hutchinson Can
cer Research Center, Seattle, Washington 98104
Tony E. Hugli (99), Department of Immunology, Research Institute of Scripps
Clinic, La Jolla, California 92037
xi
Xll Contributors
David M. Humphrey (67), Department of Pathology, University of Texas Health
Science Center at San Antonio, San Antonio, Texas 78284
Kimishige Ishizaka (185), The Johns Hopkins University School of Medicine,
The Good Samaritan Hospital, Baltimore, Maryland 21239
Ann Kagey-Sobotka (83), The Johns Hopkins University1 School of Medicine, The
Good Samaritan Hospital, Baltimore, Maryland 21239
Donald E. Kern (177), Program in Basic Immunology, Fred Hutchinson Cancer
Research Center, Seattle, Washington 98104
Victoria P. Knutson (13), Department of Physiological Chemistry, The Johns
Hopkins University School of Medicine, Baltimore, Maryland 21205
Catherine Koo (211), Laboratory of Immune Effector Function, Howard Hughes
Medical institute, Department of Medicine, Duke University Medical Center,
Durham, North Carolina 27710
M. Daniel Lane (13), Department of Physiological Chemistry, The Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205
Robert A. Lewis (49), Department of Medicine, Harvard Medical School and De
partment of Rheumatology and Immunology, Brigham and Women 's Hospital,
Boston, Massachusetts 02115
Lawrence M. Lichtenstein ( 83), The Johns Hopkins University School of Medi
cine, The Good Samaritan Hospital, Baltimore, Maryland 21239
Donald W. MacGlashan, Jr. (83), The Johns Hopkins University School of Medicine,
The Good Samaritan Hospital, Baltimore, Maryland 21239
Manfred M. Mayer (117), Subdepartment of Immunology, Department of Mole
cular Biology and Genetics, The Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205
Linda M. McManus (67), Department of Pathology, University of Texas Health
Science Center at San Antonio, San Antonio, Texas 78284
David W. Michaels (117), Miles Laboratories, Ames Division, P.O. Box 70,
Elkhart, Indiana 46515
Carl F. Nathan (221), Laboratory of Cellular Physiology and Immunology, The
Rockefeller University, New York, New York 10021
John A. Oates (41), Departments of Medicine and Pharmacology, Vanderbilt Uni
versity School of Medicine, Nashville, Tennessee 37232
Joost J. Oppenheim (163), Laboratory of Microbiology and Immunology, National
Institute of Dental Research, National Institutes of Health, Bethesda, Maryland
20205
Stephen P. Peters (83), The Johns Hopkins University School of Medicine, The Good
Samaritan Hospital, Baltimore, Maryland 21239
R. Neal Pinckard (67), Departments of Pathology and Medicine, University of Texas
Health Science Center at San Antonio, San Antonio, Texas 78284
Louise E. Ramm (117), Subdepartment of Immunology, Department of Molecular
Biology and Genetics, The Johns Hopkins University School of Medicine, Balti
more, Maryland 21205
Contributors Xlll
Gabriele V. Ronnett (13), Department of Physiological Chemistry, The Johns
Hopkins University School of Medicine, Baltimore, Maryland 21205
Robert P. Schleimer (83), The Johns Hopkins University School of Medicine, The
Good Samaritan Hospital, Baltimore, Maryland 21239
Edward S. Schulman (83), The Johns Hopkins University School of Medicine, The
Good Samaritan Hospital, Baltimore, Maryland 21239
Hyun S. Shin (241), Subdepartment of Immunology, Department of Molecular
Biology and Genetics, The Johns Hopkins University School of Medicine, Balti
more, Mary land 21205
Ralph Snyderman (211), Laboratory of Immune Effector Function, Howard Hughes
Medical Institute, Department of Medicine, Duke University Medical Center,
Durham, North Carolina 27710
J</>rgen Tranum-Jensen (141), Anatomy Institute C, University of Copenhagen,
Blegdamsvej 3C, DK-2200, Copenhagen N, Denmark
Michael B. Whitlow (117), Subdepartment of Immunology, Department of Molecu
lar Biology and Genetics, The Johns Hopkins University School of Medicine, Balti
more, Maryland 21205
Itzhak Yuli (211), Laboratory of Immune Effector Function, Howard Hughes Medi
cal Institute, Department of Medicine, Duke University Medical Center, Durham,
North Carolina 27710
Preface
A new pharmacology is being developed based upon an understanding of natural
processes for the modulation of cell metabolism, as in growth, differentiation, and
stimulation of specific function. Great progress is being made in elucidating several
aspects of these complex and important fields of study. These subjects are the focus of
the Second John Jacob Abel Symposium on Drug Development.
The response of a cell depends upon the concentration of the ligand, the number of
functional receptors available for ligand recognition and binding, and the transduc-
tion of the signal through subsequent intercellular events. Three of the most advanced
model systems instrumental in the discovery and characterization of these events are
presented in this volume: the low-density lipoprotein (LDL) receptor, the epidermal
growth factor (EGF) receptor, and the insulin receptor. The LDL receptor is a proto
type for a class of surface receptors that mediate the cellular uptake of macromole-
cules through the process of receptor-mediated endocytosis. Molecules now known
to be taken up by receptor-mediated endocytosis include polypeptide hormones,
plasma transport proteins, and a large assortment of other macromolecules that bind
to cell surface receptors. Brown and Goldstein, herein, describe the general charac
teristics of receptor-mediated endocytosis, the LDL receptor, mechanisms by which
LDL receptors reach coated pits, recycling of the LDL receptor, and functional
domains of the LDL receptor. Great interest has also recently centered on another
property of growth-related cell surface receptors: the function of these receptors as
tyrosine-specific protein kinases, similar to the protein products of some viral onco-
genes. Stanley Cohen, who has pioneered studies of the epidermal growth factor
(EGF) receptor, provides a detailed analysis of the properties of the EGF receptor as
a protein kinase. Another general consideration in receptor function is the concentra
tion of the receptor on the cell surface. Presently, the mechanisms by which the levels
of cell surface and intracellular receptor are controlled is poorly understood. In a
general sense, the number of receptors in a cell depends upon both the rates of synthe
sis and inactivation. An approach to these questions by use of heavy isotope density-
shift techniques has been developed by Dan Lane who describes the metabolism of
XV
XVI Preface
cell surface insulin receptors and the effect of insulin-induced receptor down-regula
tion.
An extraordinary family of cell mediators is derived from arachidonic acid. Arach-
idonic acid may be metabolized either via cyclooxygenase enzymes leading to the
production of prostaglandins and thromboxanes, or by lipoxy genäse pathways to
produce a hydroperoxyeicosatetraenoic acid (HPETE). HPETE may be further me
tabolized to the leukotriene family of compounds. Following the initial description in
the mid-1970s of the lipoxy genäse pathway, an explosion of interest has developed
concerning the chemistry and biology of these compounds. Lawrence M. Lichten
stein has been at the forefront of work directed toward understanding events involved
in immediate hypersensitivity. These studies, reviewed here, demonstrate that most
cells produce lipoxygenase products and suggest that these metabolites may be in
volved in mediator release from human basophils and mast cells. Selective expres
sion of some of these agents is described by John A. Oates, who reviews the discov
ery of prostaglandins D2 as the mediator of human mast cell disease, and the abun
dant production of the 15-HETE leukotrienes by eosinophiles. The biological effects
of leukotrienes are further described by Robert A. Lewis and A.W. Ford-Hutchin-
son. Interest in the lipoxygenase pathways has also been stimulated by the discovery
that the leukotriene metabolic pathways give rise to a series of products that account
for the biological activity known as slow-reacting substance. These activities include
bronchial and trachéal smooth muscle construction, vascular permeability changes,
and mucus production. Thus, the leukotrienes are thought to be important mediators
of human diseases such as asthma. Along with leukotrienes and other anaphylactomi-
metic mediators, such as histamine, serotonin, and bradykinin, a new agent, acetyl
glyceryl ether phosphorylcholine (AGEPC), is now added to the increasing number
of agents thought to be involved in acute allergic reactions. The properties of this
compound, described by R. Neal Pinckard, suggest that AGEPC must be considered
as one of the most potent anaphylactoid mediators thus far described.
Other small polypeptides capable of stimulating responses from a variety of cell
types at submicromolar levels are the anaphylatoxins C3a, C4a, and C5a, released
from complement components C3, C4, and C5 during activities of the blood comple
ment cascade. These molecules are typical inflammatory factors that play a major
role in the host defense system in hypersensitivity, autoimmunity, and inflammatory
processes in general. The chemistry and biology of these peptides is described by
Tony E. Hugh and their mechanism of action by Sucharit Bhakdi and Manfred M.
Mayer.
A number of other polypeptide factors, generally termed cytokines, which serve to
regulate the mobility, proliferation, and differentiation of target cells, are produced
by a variety of cell types, including fibroblasts, keratinocyte, and lymphoid cells.
The general properties of several of these cytokine-cell interactions that modulate
inflammatory reactions are outlined by Joost J. Oppenheim. These include nonspeci
fic cytokines (migration inhibitory factor, macrophage activation factor, leukocyte-
inhibitory factor, and osteoclast activating factor), amplification factors (colony-
stimulating factors, interleukin 2, T cell-replacing factor, interleukin 1, B cell
Preface xvii
growth factor), and suppressivefactors (interferon, soluble immune suppressive sub
stance, inhibitor of DNA synthesis, and immunoglobulin-binding factor). Some of
the best characterized of these factors are described in detail: interleukin-2, by Steven
Gillis; interferons, by Robert Friedman; and IgE-binding factors, by Kimishige Ishi-
zaka.
These cytokines and their cellular mediator mechanisms are of great interest for
their possible pharmacologie applications. Extensive studies of the effect of inter
feron have been widely described. The pharmacologie manipulation of other cyto
kines that involve macrophages and T lymphocytes are included in this volume. One
approach, described by Ralph Snyderman, addresses the biological activity of human
polymorphonuclear leukocytes by modifying the affinity of the cell receptor for the
oligopeptide chemotactic factor. Another remarkable form of communication be
tween cells is the cytotoxic effect of lymphocytes, macrophages, granulocytes, and
perhaps platelets and mast cells. Carl F. Nathan provides an overview of the role of
secretory products in cell-mediated cytotoxicity. The macrophage receives the most
attention because of recent advances in the characterization of its extensive secretory
repertoire, within which several cytotoxic factors have been identified. Lastly, Hyun
S. Shin describes the role of lipophosphatidylcholine and interleukin 1 as agents to
enhance antibody-mediated tumor suppression. The importance of such studies has
been considerably enhanced by the potential use of monoclonal antibodies in the
immunotherapy of cancer. Studies in experimental animals suggest the antibody in
cooperation with macrophages, lymphocytes, platelets, and perhaps complement can
cure an animal of tumor. Among the possible effectors, macrophages are particularly
powerful in destroying antibody-coated tumor cells. A limiting feature, the failure to
cure large tumors, appears to result from a local impairment of macrophage chemo-
taxis or from a failure of accumulated macrophages to become cytotoxic to tumor
cells. Two agents that may enhance macrophage response are lysophosphatidylcho-
line, a chemoattractant for lymphocytes, and interleukins 1, a factor produced by
activated macrophages that stimulates the production of interleukin 2, which in turn
drives the T cell mitogenic response.
