Guide to Signal Pathways in Immune Cells (eBook)

Preface 5
Contents 7
List of Figures 15
List of Tables 20
Cellular Activation Processes 22
1.1 Membrane Receptors and Second Messengers 22
1.2 Examples of Plasma Membrane Receptors 23
1.3 G Proteins: Guanine Nucleotide Coupling 24
1.4 Control over GPCRs: G Protein-Coupled Receptor Kinases, Arrestins, Regulators of G Protein Signaling Proteins, and GPCR Interacting Proteins 26
References 29
Cell Membrane Receptors and Phospholipids 32
2.1 Turnover of Cell Membrane Phosphatidyl-Inositol 32
2.1.1 Phospholipase C (PLC) 32
2.1.2 Diacylglycerol 33
2.1.3 Protein Kinase C 34
2.2 The Phosphatidyl-Inositol Phosphates 34
2.3 Phosphoinositide 3 Kinases 36
2.3.1 PI3K Effector Proteins 38
2.4 Protein Kinase B (Survival Kinase Akt) 40
2.5 Calcium Ions as Second Messenger 40
2.6 Desensitisation of Membrane Receptors 42
References 42
Platelet Aggregation and Its Control 45
3.1 Platelet Aggregation 45
3.2 Platelet Adhesion to Collagen 48
3.3 Platelets and Immunity 49
3.4 Constitutive and Inducible NO Synthetases 50
3.5 Nitric Oxide and the Immune System 51
References 52
Introduction to Signalling Cascades 56
4.1 Serine/Threonine Kinases 56
4.2 Mitogen-Activated Protein Kinases and Signalling Cascades 56
4.2.1 Organisation by Scaffold Proteins 59
4.2.2 Redox Regulation of Signal Transduction 60
4.2.3 c-Jun N-terminal Kinases 60
4.2.4 p38 MAP Kinases 61
4.2.5 The ERK Cassette 63
4.2.6 Cascade Control by Phosphatases 63
4.3 Transcription Factors and DNA-Binding Domains 65
4.3.1 More About Histone Acetylation 67
4.4 Formation of Enhanceosomes on Gene Promoters and Enhancers 68
4.4.1 Cytokine Genes 68
4.4.2 The IFN b Enhanceosome 70
4.4.3 Chromatin Remodelling and Epigenetics 71
4.4.4 Control of IL-4 and IL-13 Production (Th2 Cytokines) 72
4.4.5 The Anti-inflammatory Action of PPAR g s and Retinoids 73
4.4.6 Estrogen Receptors 75
4.4.7 Corticosteroid Receptors 76
4.5 DNA Methylation and Gene Control (Epigenetics) 77
4.5.1 c-Myc and Cell Proliferation 79
4.5.2 Forkhead Transcription Factors (Foxos) 79
4.6 Differential Gene Expression Patterns 81
4.7 A Note about Ubiquitination 81
4.7.1 Sumoylation and Gene Repression 83
4.8 Notch Signalling in Haemopoiesis 83
4.9 Hypoxia-Inducing Factor 84
4.10 Vascular Endothelial Growth Factor 85
References 86
Cell Proliferation 95
5.1 Ras as a GTP-Binding Protein and GTPase 95
5.1.1 Other Small GTPases 96
5.2 Cell Proliferation in Response to PDGF 97
5.3 Caveolae and Lipid Rafts 99
5.4 Protein Modules 100
5.5 Protein Tyrosine Kinases 101
5.5.1 Janus Gateway Phosphotyrosine Kinases 102
5.5.2 Transactivation 102
5.6 Abl and Bcr-Abl 102
5.7 Control Over Smooth Muscle Cell Proliferation 103
5.8 Angiotensin II and Smooth Muscle Cells 103
5.9 Endothelin-1 and Its Action 105
References 106
Mast Cell Activation and the Role of Eicosanoids 109
6.1 Signal Transduction in Mast Cells 109
6.2 The Formation of Eicosanoids 111
6.2.1 The Formation of Prostaglandin E2 112
6.3 Mast Cell Degranulation 113
6.4 Cyclic AMP Downregulates Activation of Immune Cells 114
6.5 Cyclic AMP and Cell Proliferation 114
6.6 The b c Cytokine Receptors and CREB Control of Growth 114
6.7 Other Modulators of Mast Cell Degranulation 115
References 115
Lipid Products and Cell Signaling 118
7.1 Phosphatidic Acid as a Second Messenger 118
7.2 Protein Kinase D 118
7.3 Sphingolipids as Regulators of Cell Signalling 120
7.4 Sphingomyelin Metabolites/Cell Proliferation/Apoptosis 122
7.5 Lysophosphatidic Acid as Serum Growth Factor 123
7.6 Antineutrophil Cytoplasmic Antibody-Stimulated Neutrophil Adhesion 124
References 124
Programmed Cell Death: Apoptosis 127
8.1 Apoptosis Mechanisms 127
8.1.1 Determinants of Apoptosis 130
8.1.2 Heat Shock Proteins and Apoptosis 131
8.2 Cellular Metabolism and Apoptosis 131
8.2.1 Endoplasmic Reticulum Stress 132
8.3 Inflammatory Caspases 132
8.4 Effect of Apoptotic Cells on Macrophages 133
8.5 Apoptosis of Neutrophils 133
8.6 Apoptosis of T Lymphocytes 134
8.7 Apoptosis of Dendritic Cells or Macrophages 134
8.8 Cell Death via Fas or TNFRI Receptors 135
8.8.1 Death Receptor Functioning: Complexes I/II 136
8.9 Detecting Apoptosis 136
8.10 DNA Damage Leading to Cell Cycle Arrest or Apoptosis 137
8.11 Apoptosis versus Carcinogenesis 139
References 140
Control of the Cytoskeleton 145
9.1 The LowMolecular Weight Monomeric GTPases 145
9.2 Rho GTPases 146
9.3 Actin Bundles in Neutrophils 148
9.4 Cell Migration 151
9.5 The Mechanics of Phagocytosis 152
9.6 Endocytosis 153
9.7 Exocytosis: Discharge of Vesicles 154
9.7.1 Interleukin 8 Chemokine and Discharge of Neutrophil Granules 156
9.8 Cell Adhesion Receptors and the Cytoskeleton 156
9.8.1 Signalling from Integrins 156
9.8.2 Detail about Focal Adhesion Kinase 159
9.8.3 Signalling from Immunoglobulin CAMs 160
9.8.4 Signalling from Selectins 160
9.8.5 Cadherins and Adhesion of Epithelial Cells 161
9.9 The Use of Statins 162
References 162
Leucocyte Activation and Behaviour 168
10.1 Activation of Neutrophils 168
10.1.1 Ca 2± Balance and Neutrophils 171
10.2 Neutrophil Hyperactivation 172
10.2.1 Stimulation of Phagocytes by Colony- Stimulation Factors 173
10.3 Fc Receptor-Mediated Phagocytosis 174
10.4 Movement of Leucocytes in Response to Chemoattractants 177
10.5 Activation of Eosinophils 179
10.6 Integrin-Mediated Adhesion of Phagocytes 180
10.7 Integrin LFA-1 as Regulator of Leucocyte Adhesion 182
10.8 Th17 cells via IL-17 drive neutrophils and inflamation 182
10.9 Communication between Neutrophils and Dendritic Cells 183
References 183
Cell Defence and Survival 189
11.1 Transcription Factor NF-kappa 189
11.1.1 The Classical Canonical NF- k B Pathway 191
11.1.2 The Alternative Noncanonical Pathway 193
11.1.3 More about NF- k B Control 194
11.2 How to Inhibit NF- k B 196
11.3 Gene Knockout or Transgenic Experimental Animals 197
11.4 The Control of Cyclooxygenase 2 198
11.5 PPAR g and PPAR a in Inflammation and Immunity 200
11.6 Cell Survival: Akt and Glycogen Synthase Kinase 3 201
11.7 Insulin Receptors 202
11.8 Cross-Talk between Insulin Signalling and the Angiotensin II System 204
11.9 Understanding mTOR 205
11.10 Alveolar Macrophage Survival 207
References 207
Signalling in Immune Reactions 214
12.1 The Immune Response 214
12.1.1 Dendritic Cells 215
12.1.2 Macrophage Types: MIMicrobicidal, M2 Regulatory or M2” Would Healing 216
12.1.3 Toll-Like Receptors 217
12.1.4 Negative Regulation of Toll-Like Receptors 220
12.1.5 Inside Sensors for Outside Pathogens: Nucleotide Oligomerisation Domain- Like Receptors 221
12.1.6 Production of Interleukin 1 223
12.2 Cytokines and the Immune Response 224
12.3 Activation of Macrophages 226
12.3.1 Control of Macrophages 228
12.4 Lipopolysaccharide Stimulation of Macrophages ( or Endothelial Cells) 229
12.4.1 Negative Regulators of LPS Activation and TLR Receptor Signalling 230
12.4.2 Interaction IFN g /TLR Signalling in Macrophages 231
12.5 Dendritic Cells 231
12.6 Signalling by TNF 233
12.7 Macrophage Migration Inhibitory Factor 235
12.8 Cytokines and Growth Factors 236
12.8.1 Receptors for Cytokines and Cellular Activation 236
12.8.2 IL2Receptor and IL-2 237
12.8.3 Transpresentation of IL-15 239
12.8.4 Negative Regulation of Cytokine Receptors 240
12.9 Connections by Jak-Stats 240
12.10 Activation of Macrophages by IL-1 and TNF 242
12.11 TRAF Adapter Proteins 242
12.12 CD40 Signalling 244
12.13 Other TNFR Superfamily Molecules 244
12.14 RAGE Receptors and Cytokine Production 245
12.15 IL-10 Immunomodulatory Cytokine 246
12.16 Those Basic Signal Cascades 247
References 249
T Lymphocytes 260
13.1 Activation of T Lymphocytes 260
13.1.1 General Scheme of T Lymphocyte Activation 261
13.1.2 Adaptor Proteins 265
13.1.3 CD28 Costimulation 266
13.1.4 NF- k B Activation and T Cell Co-stimulation 268
13.2 Control of Lymphocyte Activation by Phosphatases 269
13.3 Downregulation of T Lymphocyte Activation 270
13.3.1 The SLE CD4 T Lymphocyte 272
13.4 Characteristics of Forms of T Lymphocyte 273
13.4.1 Effector T Lymphocytes 273
13.4.2 CD8 Cytotoxic T Lymphocytes 273
13.4.3 Memory T Cells (CD4 and CD8) 274
13.4.4 Th17 Inflammatory cells 275
13.4.5 T Cell Apoptosis 275
13.4.6 Anergic CD4 T Cells 276
13.4.7 Quiescence of T Cells 279
13.4.8 Suppression of T Cells 279
13.4.9 T Regulatory Lymphocytes (nTreg, iTreg, Tr-1) 280
13.5 Th1 and Th2 Lymphocytes 281
13.5.1 Interleukin 12 Signalling and Th1 Lymphocytes 283
13.5.2 Regulation of IFN g Production 284
13.5.3 Th17 Inflammatory Cells 285
13.6 Interleukin 4 and Th2 Lymphocytes 286
13.6.1 Interleukin 13 286
13.7 Respiratory Tract Allergy 287
13.8 Chronic Bronchitis as Obstructive Airway Disease 290
References 290
Immunological Controls 306
14.1 Transforming Growth Factor- ß Signalling 306
14.1.1 Smad Activity and Other Kinase Pathways 307
14.1.2 TGF b and Immune Regulation 309
14.1.3 TGF b Inhibition of Cell Growth 310
14.1.4 TGF b and Inhibition of Cell Proliferation 310
14.1.5 TGF b and Apoptosis 310
14.2 Clinical Implications 311
14.2.1 TGF b , Connective Tissue Growth Factor, and Fibrosis 311
14.2.2 Connective Tissue Growth Factor 311
14.2.3 Scleroderma 312
14.2.4 TGF b Is Anti-inflammatory 312
14.3 TGF b and Cancer 313
14.4 Bone Morphogenetic Proteins 314
14.5 The Actions of Interferons 314
14.6 Signalling by IFN 315
14.7 Signalling by IFN 317
14.7.1 Controlling Viruses 318
14.7.2 Plasmacytoid Dendritic Cells 319
14.8 SOCS: Negative Regulation of the Jak-Stat Pathway 320
14.8.1 Regulation of the Jak-Stat Pathways 322
14.9 Negating Cytokines 322
14.10 Prostaglandin E2 and T Cell Modulation 323
14.11 Interleukin 4 Signalling 323
14.12 Interleukin 13 325
14.13 Decoy Receptors 325
References 326
Natural Killer Cells 336
15.1 Receptors for HLA Class I 336
15.1.1 Hyporesponsiveness of NK Cells 338
15.2 ITAMs and NK Cell Receptors 339
15.3 ITIMs and NK Cell Receptors 340
15.4 NK Cells in Action 341
15.5 Signalling Lymphocyte Activation Molecule and Adapter SAP 343
15.6 NKT Cells 344
15.7 KIRs and KARs on T Cells 344
15.8 ILT Molecules on Regulatory Cells 345
References 345
B Lymphocytes 349
16.1 B Cell Receptor Signalling 349
16.2 Negative Signalling on B Lymphocytes 352
16.3 CD40 Signalling 353
16.4 Sustaining B Cells with B Cell-Activating Factor (BLys) 353
16.5 Apoptosis of B Lymphocytes 354
16.6 Control Over B Cell Proliferation 355
16.7 B Cell Development 355
16.8 B Cell Tolerance 357
16.9 Epstein-Barr Virus and B Cell Proliferation 358
16.10 B Cells of Chronic Lymphatic Leukaemia 359
16.11 The Lymphomas 359
16.12 Plasma Cells in Multiple Myeloma 360
References 361
The Cell Cycle 366
17.1 Control of the Cell Cycle 366
17.2 PI3K and Cell Proliferation 370
17.2.1 Notch and Cell Proliferation 370
17.3 Integrins and Cell Proliferation 370
17.4 C-Myc and Cell Proliferation 371
17.5 The Cell Cycle and DNA Damage 371
17.6 p53 Tumour Suppressor 373
17.7 Control of the Cell Cycle Checkpoints 373
17.8 The Cell Cycle of T Lymphocytes 374
17.9 Liver Regeneration 375
17.10 Tumours and the Cell Cycle 375
17.11 Cell Renewal and Hh Signalling 376
17.12 Wnt Signalling 377
References 379
Cancer 384
18.1 Cancer Cells 384
18.2 Multistage Carcinogenesis in Skin 388
18.3 Breast Cancer 389
18.4 Prostate Cancer 394
18.5 Cadherins and Catenins 396
18.6 Ovarian Cancers 397
18.7 Renal Cancer 399
18.8 Colon Cancer 399
18.9 Epithelial-Mesenchymal Transition 403
18.10 Genes for Metastasis 403
References 405
Index 415