JOHN 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 A Subsidiary of Harcourt Brace Jovanovich, Publishers NEW YORK LONDON PARIS SAN DIEGO SAN FRANCISCO SAO PAULO SYDNEY TOKYO TORONTO 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. ALL RIGHTS RESERVED. NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER. ACADEMIC PRESS, INC. 111 Fifth Avenue, New York, New York 10003 United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road, London NW1 7DX 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.