Cellular and Molecular Aspects of Inflammation

The characterization of the cellular and molecular mechanisms that mediate inflammation provides a foundation that supports future studies that will de­ fine mechanisms more intimately. It encourages substantial optimism about the opportunities to understand the inflammatory process and to use that information to develop novel therapeutic approaches. Recent progress has defined the cells that mediate the inflammatory response, many of the inter­ cellular transmitters, the receptors, signal transduction processes and regula­ tory mechanisms. Thus, we now have the opportunity to understand inflammation in pharmacologic terms and to attack the key molecular targets to develop new therapeutics. Among the cells involved in the inflammatory response are the lympho­ cytes, neutrophils and endothelial cells. Maintenance of homeostasis, re­ sponse to proinflammatory stimuli and pathophysiologic responses are products of complex interactions between these and other elements of the immune systems. Each of these cells displays a variety of receptors to define the stimuli to which they respond. The receptors displayed that the signal transduction processes and cellular responses are regulated genetically and epigenetic ally . The critical role of membranes and particularly the phospho­ lipid components of the membranes is emphasized by recent studies.

I. Cellular Interactions in Inflammatory Processes.- 1 Cellular Interactions Regulating Inflammation: Activation of T Lymphocytes at Inflammatory Sites and Their Role in Perpetuating Chronic Inflammation.- 1. Introduction.- 2. Antigen-Induced T Cell Activation.- 3. Cellular Interactions Involved in the Initiation of T Cell Activation.- 4. CD2, CD11a, and HLA-A, B, C Molecules Are Involved in T Cell—Accessory Cell Interactions that Promote T Cell Responses.- 5. The Role of CD 5 and CD 28 in T Cell Activation.- 6. The Role of CD4 in T Cell Proliferation.- 7. Proposed Model of the Signals Involved in T Cell Activation.- 8. Conclusions.- References.- 2 Triggering and Activation of Human Neutrophils: Two Aspects of the Response to Transmembrane Signals.- 1. Phospholopid Remodeling and Intracellular Messengers.- 2. Phospholipase A Activation in Neutrophils.- 3. Arachidonate Metabolism.- References.- 3 Neutrophil Emigration: Quantitation, Kinetics, and the Role of Mediators.- 1. Introduction.- 2. Quantitation and Kinetics.- 3. Mediators of Neutrophil Emigration.- 4. Conclusions.- References.- 4 The Role of Endothelium in Chronic Inflammation.- 1. Introduction.- 2. Lymphocyte—Rich and Transitional Areas of Synovial Membrane and Lymph Node.- 2.1. Steps in Lymphocyte Emigration.- 2.2. T Cell to Endothelial Cell Binding.- 2.3. Effect of Cytokines on T Cell to Endothelial Cell Binding.- 2.4. Effect of Lipopolysaccharide on T Cell to Endothelial Cell Binding.- 2.5. Chemotaxis in the Emigration of Lymphocytes from the Postcapillary Venule.- 2.6. Production of IL-1 by Human Endothelial Cells.- 2.7. Mechanisms of T Cell—Endothelial Cell Interaction.- 3. Discussion.- References.- II. Peptide Mediators of Inflammation.- 5 Peptide Mediators of Inflammation: An Overview.- 6 Interleukin-1: Biology and Molecular Biology.- 1. Introduction.- 2. IL-1 and T Cell Activation.- 3. IL-1 Receptor Studies.- 4. IL-1 Secretion and Extracellular Processing.- 5. Membrane IL-1.- 6. IL-1 and Inflammatory Cells.- 7. Unanswered Questions.- References.- 7 Structure—Function Relations for the Interleukin-2 Receptor.- 1. A Molecular Explanation for the Different Affinities of the IL-2 Receptor.- 1.1. High-and Low-Affinity IL-2 Binding Sites: Role of the Tac (Alpha) Protein.- 1.2. The Two-Chain Hypothesis for the High-Affinity IL-2 Receptor.- 1.3. Characterization of a Novel IL-2 Binding Molecule (Beta).- 1.4. Evidence that High-Affinity Binding Is the Result of an Alpha—IL-2—Beta Complex.- 2. Multiple Forms of the IL-2 Receptor: Function and Cellular Distribution.- 2.1. Type I Receptors: The Alpha (Tac) Chain.- 2.2. Type II Receptors: The Beta Chain.- 2.3. Type III Receptors: The Alpha—IL-2—Beta Complex.- 3. Ligand Binding and the Structure of the Tac Receptor Protein.- 3.1. Localization of the IL-2 Binding Site.- 3.2. Ligand Binding by Tac Protein Variants.- 3.3. Disulfide Structure of the Tac Protein.- 3.4. Sequence Analysis of Soluble Tac Protein.- 4. Concluding Remarks.- References.- 8 Cachectin (Tumor Necrosis Factor): A Macrophage Protein that Induces a Catabolic State and Septic Shock in Infected Animals.- 1. Introduction.- 2. The Parallel Histories of Cachectin and Tumor Necrosis Factor.- 3. Structure of the Cachectin/TNF Peptide, Message, and Gene.- 3.1. Several Mammalian Species Express Homologous Cachectins as Prohormones.- 3.2. Cachectin Genes Exhibit Potential Regulatory Features.- 4. Regulation of Expression and Correlation with Disease States.- 4.1. Bacterial, Viral, and Protozoal Stimuli Induce Cachectin.- 4.2. Dexamethasone, IFN-?, and the 1psd Mutation Regulate Cachectin.- 4.3. Characterization and Biodistribution of the Systemic Cachectin Response.- 4.4. Infusion of Cachectin Closely Mimics Endotoxemia.- 4.5. Cachectin in Disease States.- 5. Cachectin/TNF Receptor and Mechanism of Action.- 6. Biological Activities: Parallels between Disease States, in Vitro Effects, and in Vivo Models.- 6.1. Adipocytes.- 6.2. Skeletal Muscle and Muscle Cell Lines.- 6.3. Endothelial Cells, Procoagulant Activity, and Leukocyte Adhesion.- 6.4. Bone, Cartilage, and Fibroblasts.- 6.5. Liver and Hepatocytes.- 6.6. Leukocytes.- References.- III. Biosynthesis and Release of Lipid Mediators of Inflammation.- 9 Arachidonic Acid Metabolism in Tissue Injury.- 1. Introduction.- 2. Exaggerated Eicosanoid Production in Hydronephrosis.- 2.1. Arachidonic Acid Metabolism in Normal and Hydronephrotic Kidney.- 2.2. Accumulation of Inflammatory Cells in Hydronephrosis.- 2.3. Role of Tissue Macrophages.- 2.4. Monokines.- 2.5. Production of Leukotrienes in Hydronephrosis.- 3. Essential Fatty Acid Deficiency and Arachidonic Acid Metabolism in Inflammation.- 3.1. Biochemical Effects.- 3.2. Functional Effects.- 3.3. Effect of EFA Deficiency on Hydronephrosis.- 4. Arachidonic Acid Metabolism in Myocardial Infarction.- 4.1. Eicosanoid Production in Rabbit Myocardial Ischemia.- 4.2. Biochemical, Morphological, and Anatomical Considerations.- References.- 10 Lipoxygenase Metabolites: Chemistry and Biochemistry.- 1. Introduction.- 2. General Overview.- 3. Specific Examples.- 3.1. Determination of Structure and Biosynthesis: The Lipoxins.- 3.2. Analogues as Probes for Structural Specificity.- 3.3. Determination of in Vivo Metabolism of the Peptido-Leukotrienes.- 4. Conclusions.- References.- IV. Molecular Intermediates in Signal Transductions.- 11 Guanine Nucleotide Regulatory Proteins in Inflammatory and Immune Responses.- 1. Introduction.- 2. General Aspects of G-Protein Structure and Function.- 2.1. Receptor—Effector Coupling and the GTPase Cycle.- 2.2. Subunit Structure.- 2.3. Subcellular Localization.- 2.4. Effects of Bacterial Toxins.- 3. Specific G Proteins and Their Functions.- 3.1. Gs and Gi.- 3.2. Gpi.- 3.3. Other G Proteins.- 4. Molecular Biology of G-Proteins.- 5. Specificity of Receptor—Effector Coupling by G Proteins.- 6. Regulation of G Protein Function.- 7. G Proteins in Inflammatory and Immune Responses.- 7.1. G Proteins in Neutrophils.- 7.2. G Proteins in Lymphocytes and Macrophages.- 8. Conclusions.- References.- 12 Regulation of Phosphoinositide Breakdown.- 1. Introduction.- 2. Phosphoinositide Metabolism.- 3. Receptors for Calcium-Mobilizing Agonists.- 4. Role of Guanine Nucleotide Binding Proteins in Agonist Regulation of Phosphoinositide Breakdown.- 5. Growth Factors and Phosphoinositide Metabolism.- 6. Agonist-Regulated Phosphoinositide Phospholipase C.- 7. Summary.- References.- 13 Regulation of Protein Kinase C by Sphingosine/Lysosphingolipids.- 1. Introduction.- 1.1. Discovery of Protein Kinase C and sn-1, 2-Diacylglycerol Second Messengers.- 1.2. Phorbol Ester Receptor and Tumor Promotion.- 1.3. Signal Transduction: Growth Factors, Neurotransmitters, and Hormones.- 1.4. Oncogene Products and Signal Transduction.- 1.5. Scope and Content.- 2. Structure, Function, and Regulation of Protein Kinase C.- 2.1. Cell-Permeable DAGs and DAG Analogues.- 2.2. Quantitation of DAG Second Messengers.- 2.3. Cloning and Expression of Multiple Rat Brain Protein Kinase C cDNAs.- 2.4. Domain Structure of Protein Kinase C.- 2.5. Mechanism of Regulation by PS, Ca2+, DAG (Phorbol Esters): Mixed Micellar Analysis.- 3. Sphingosine/Lysosphingolipid Inhibition of Protein Kinase C.- 3.1. Inhibition in Vitro.- 3.2. Inhibition of Protein Kinase C in Cells by Sphingosine.- 3.3. Hypothesis.- References.- 14 Regulation of Inositol Trisphosphate Formation and Action.- 1. Introduction.- 2. Control of Phospholipase C.- 2.1 Guanine Nucleotides.- 2.2 Calcium.- 2.3 Receptors.- 3. Metabolism of Inositol 1,4,5-Trisphosphate.- 4. Actions of Inositol Phosphates.- 4.1 Calcium Release.- 4.2 Calcium Entry.- 5. Conclusions.- References.- V. Receptors and Signal Transduction Processes Involved in Inflammation.- 15 Molecular Properties of Leukocyte Receptors for Leukotrienes.- 1. Introduction.- 2. Specificity and Affinity of Human Leukocyte Receptors for Leukotrienes.- 3. Subcellular Distribution of Leukotriene Receptors of Human PMN Leukocytes.- 4. Structural Properties of the Leukotriene Receptors.- 5. Biochemical Transduction of Signals from Leukocyte Receptors for Leukotrienes.- 6. Antibodies to Leukotriene Receptors.- 7. Development of Leukotriene Receptors During Differentiation of Leukocytes.- 8. Clinical Implications.- References.- 16 LTD4 Receptors and Signal Transduction Processes.- 1. Introduction.- 2. The LTD4 Receptors.- 3. The Guanine Nucleotide Binding Proteins.- 4. The PI-Phospholipase C.- 5. Inositol Phosphate Metabolism.- 6. Calcium Mobilization.- 7. Protein Kinase C.- 8. Phospholipase A2 Activating Protein.- 9. 5—Lipoxygenase—LTA4 Synthetase.- 10. Epigenetic Regulation.- 11. Genetic Regulation.- 12. Conclusion.- References.- 17 Characterization of Thromboxane A2/Prostaglandin H2 Receptors.- 1. Introduction.- 2. Platelet and Vascular Thromboxane A2 Receptors.- 2.1 Pharmacologic Identification of Subclasses of Receptors.- 3. Radioligand Binding Studies.- 4. Second Messenger Systems.- 4.1. Platelets.- 4.2. Vascular Smooth Muscle.- 5. Summary.- References.- 18 Chemoattractant Receptors and Signal Transduction Processes.- 1. Introduction.- 2. Chemoattractant Receptors.- 3. Receptor/GTP-Binding protein/Phospholipase C Pathway.- 4. Characterization of the GTP-Binding Protein Involved in Leukocyte Activation.- 5. Calcium Mobilization and Inositide Metabolisn in Leukocytes.- 6. Diacylglycerol and Protein Kinase C Involvement.- 7. Termination of Chemoattractant Responses.- 8. Summary.- References.- 19 The Molecular Biology of the Human Interleukin-2 Receptor.- 1. Introduction.- 2. Identification of Anti-IL-2 Receptor Monoclonal Antibodies.- 3. IL-2 Receptor (Tac) Biosynthesis.- 4. Molecular Cloning of IL-2 Receptor (Tac) cDNAs.- 5. The IL-2 Receptor (Tac) Gene.- 6. Expression of Multiple IL-2 Receptor (Tac) mRNAs.- 7. High- and Low-Affinity Receptors for IL-2.- 8. HTLV-I, IL-2 Receptors, and the Adult T Cell Leukemia.- 9. Human Immunodeficiency Virus, Interleukin-2, and the Acquired Immune Deficiency Syndrome.- 10. Summary.- References.- VI. The Role of Phospholipases in Inflammation.- 20 Some Novel Phospholipase C Activities: Actions on Phosphatidylcholine and on Phosphatidylinositol—Glycans as Anchors for Membrane Proteins and as Precursors for Possible Insulin Mediators.- 21 Enzymatic Mechanisms and Inhibition of Phospholipase A2: From Manoalide to the Lipocortins.- 1. Introduction.- 2. Competitive Inhibitors.- 3. Irreversible Inhibitors.- 4. Lipocortins.- References.- 22 Molecular Mechanism of Regulation of Cellular Phospholipases.- 1. Introduction.- 2. Inhibition of Cellular Phospholipase(s) by Glucocorticoids.- 2.1. Inhibition of Arachidonic Acid Release.- 2.2. Properties of Lipocortins.- 2.3. Inhibition of Phospholipases by Lipocortins.- 3. Evidence for the Complex of Lipocortins with Phospholipases Inside Cells.- 3.1. Calcium and Phospholipases.- 3.2. Digestion of Lipocortins by Proteases.- 3.3. Phosphorylation of Lipocortins.- 3.4. N(G) Proteins and Lipocortins, GTP-Binding Proteins.- 4. Summary.- References.- 23 The Metabolism of Inositol Phosphates.- 1. Introduction.- 2. Phospholipase C.- 3. Substrate Specificity.- 4. Guanine Nucleotide Binding Proteins.- 5. Inositol Phosphates.- 6. Ins(I,3,4) P3and Ins(I,3,4,5)P4.- 7. Inositol Bisphosphate Metabolism.- 8. Inositol(1,4,5)P3 5-Phosphomonoesterase.- 9. Future Challenges.- References.