Guide to Signal Pathways in Immune Cells Book

1 Cellular Activation Processes 1

1.1 Membrane Receptors and Second Messengers 1

1.2 Examples of Plasma Membrane Receptors 2

1.3 G Proteins: Guanine Nucleotide Coupling 3

1.4 Control over GPCRs: G Protein-Coupled Receptor Kinases, Arrestins, Regulators of G Protein Signaling Proteins, and GPCR Interacting Proteins* 5

References 8

2 Cell Membrane Receptors and Phospholipids 11

2.1 Turnover of Cell Membrane Phosphatidyl-Inositol 11

2.1.1 Phospholipase C (PLC) 11

2.1.2 Diacylglycerol 12

2.1.3 Protein Kinase C 13

2.2 The Phosphatidyl-Inositol Phosphates 13

2.3 Phosphoinositide 3 Kinases 15

2.3.1 P13K Effector Proteins 17

2.4 Protein Kinase B (Survival Kinase Akt) 19

2.5 Calcium Ions as Second Messenger 19

2.6 Desensitisation of Membrane Receptors 21

References 21

3 Platelet Aggregation and Its Control 25

3.1 Platelet Aggregation 25

3.2 Platelet Adhesion to Collagen 28

3.3 Platelets and Immunity 29

3.4 Constitutive and Inducible NO Synthetases 30

3.5 Nitric Oxide and the Immune System 31

References 32

4 Introduction to Signalling Cascades 37

4.1 Serine/Threonine Kinases 37

4.2 Mitogen-Activated Protein Kinases and Signalling Cascades 37

4.2.1 Organisation by Scaffold Proteins* 40

4.2.2 Redox Regulation of Signal Transduction 41

4.2.3 c-Jun N-terminal Kinases 41

4.2.4 p38 MAP Kinases 42

4.2.5 The ERK Cassette 44

4.2.6 Cascade Control by Phosphatases 44

4.3 Transcription Factors and DNA-Binding Domains 46

4.3.1 More About Histone Acetylation* 48

4.4 Formation of Enhanceosomes on Gene Promoters and Enhancers* 49

4.4.1 Cytokine Genes 49

4.4.2 The IFNβ Enhanceosome 51

4.4.3 Chromatin Remodelling andEpigenetics 52

4.4.4 Control of IL-4 and IL-13 Production (Th2 Cytokines) 53

4.4.5 The Anti-inflammatory Action of PPARγs and Retinoids 54

4.4.6 Estrogen Receptors 56

4.4.7 Corticosteroid Receptors 57

4.5 DNA Methylation and Gene Control (Epigenetics)* 58

4.5.1 c-Myc and Cell Proliferation 60

4.5.2 Forkhead Transcription Factors (Foxos)* 60

4.6 Differential Gene Expression Patterns 62

4.7 A Note about Ubiquitination 62

4.7.1 Sumoylation and Gene Repression* 64

4.8 Notch Signalling in Haemopoiesis* 64

4.9 Hypoxia-Inducing Factor* 65

4.10 Vascular Endothelial Growth Factor 66

References 68

5 Cell Proliferation 77

5.1 Ras as a GTP-Binding Protein and GTPase 77

5.1.1 Other Small GTPases 78

5.2 Cell Proliferation in Response to PDGF 79

5.3 Caveolae and Lipid Rafts 81

5.4 Protein Modules 82

5.5 Protein Tyrosine Kinases 83

5.5.1 Janus Gateway Phosphotyrosine Kinases 84

5.5.2 Transactivation 84

5.6 Abl and Bcr-Abl* 84

5.7 Control Over Smooth Muscle Cell Proliferation 85

5.8 Angiotensin II and Smooth Muscle Cells 85

5.9 Endothelin-1 and Its Action 87

References 88

6 Mast Cell Activation and the Role of Eicosanoids 91

6.1 Signal Transduction in Mast Cells 91

6.2 The Formation of Eicosanoids 93

6.2.1 The Formation of Prostaglandin E2 94

6.3 Mast Cell Degranulation 95

6.4 Cyclic AMP Downregulates Activation of Immune Cells 96

6.5 Cyclic AMP and Cell Proliferation* 96

6.6 The βc Cytokine Receptors and CREB Control of Growth* 96

6.7 Other Modulators of Mast Cell Degranulation* 97

References 97

7 Lipid Products and Cell Signaling 101

7.1 Phosphatidic Acid as a Second Messenger 101

7.2 Protein Kinase D 101

7.3 Sphingolipids as Regulators of Cell Signalling* 103

7.4 Sphingomyelin Metabolites/Cell Proliferation/Apoptosis* 105

7.5 Lysophosphatidic Acid as Serum Growth Factor 106

7.6 Antineutrophil Cytoplasmic Antibody-Stimulated Neutrophil Adhesion 107

References 107

8 Programmed Cell Death: Apoptosis 111

8.1 Apoptosis Mechanisms 111

8.1.1 Determinants of Apoptosis 114

8.1.2 Heat Shock Proteins and Apoptosis 115

8.2 Cellular Metabolism and Apoptosis 115

8.2.1 Endoplasmic Reticulum Stress 116

8.3 Inflammatory Caspases 116

8.4 Effect of Apoptotic Cells on Macrophages 117

8.5 Apoptosis of Neutrophils 117

8.6 Apoptosis of T Lymphocytes 118

8.7 Apoptosis of Dendritic Cells or Macrophages 118

8.8 Cell Death via Fas or TNFRI Receptors* 119

8.8.1 Death Receptor Functioning: ComplexesI/II* 120

8.9 Detecting Apoptosis 120

8.10 DNA Damage Leading to Cell Cycle Arrest or Apoptosis 121

8.11 Apoptosis versus Carcinogenesis 123

References 124

9 Control of the Cytoskeleton 129

9.1 The LowMolecular Weight Monomeric GTPases 129

9.2 Rho GTPases 130

9.3 Actin Bundles in Neutrophils 132

9.4 Cell Migration 135

9.5 The Mechanics of Phagocytosis 136

9.6 Endocytosis 137

9.7 Exocytosis: Discharge of Vesicles 138

9.7.1 Interleukin 8 Chemokine and Discharge of Neutrophil Granules 140

9.8 Cell Adhesion Receptors and the Cytoskeleton 140

9.8.1 Signalling from Integrins 140

9.8.2 Detail about Focal Adhesion Kinase 143

9.8.3 Signalling from Immunoglobulin CAMs 144

9.8.4 Signalling from Selectins 144

9.8.5 Cadherins and Adhesion of Epithelial Cells 145

9.9 The Use of Statins 146

References 146

10 Leucocyte Activation and Behaviour 153

10.1 Activation of Neutrophils 153

10.1.1 Ca2±Balance and Neutrophils 156

10.2 Neutrophil Hyperactivation 157

10.2.1 Stimulation of Phagocytes by Colony-Stimulation Factors 158

10.3 FcReceptor-Mediated Phagocytosis 159

10.4 Movement of Leucocytes in Response to Chemoattractants 162

10.5 Activation of Eosinophils 164

10.6 Integrin-Mediated Adhesion of Phagocytes 165

10.7 Integrin LFA-1 as Regulator of Leucocyte Adhesion 167

10.8 Th 17 cells via IL-17 drive neutrophils and inflamation 167

10.9 Communication between Neutrophils and Dendritic Cells 168

References 168

11 Cell Defence and Survival 175

11.1 Transcription Factor NF-kappa 175

11.1.1 The Classical Canonical NF-κB Pathway 177

11.1.2 The Alternative Noncanonical Pathway* 179

11.1.3 More about NF-κB Control* 180

11.2 How to Inhibit NF-κB 182

11.3 Gene Knockout or Transgenic Experimental Animals 183

11.4 The Control of Cyclooxygenase 2 184

11.5 PPARγ and PPARα in Inflammation and Immunity 186

11.6 Cell Survival: Akt and Glycogen Synthase Kinase 3 187

11.7 Insulin Receptors 188

11.8 Cross-Talk between Insulin Signalling and the Angiotensin II System 190

11.9 Understanding mTOR 191

11.10 Alveolar Macrophage Survival 193

References 193

12 Signalling in Immune Reactions 201

12.1 The Immune Response 201

12.1.1 Dendritic Cells 202

12.1.2 Macrophage Types (M1 Are CD14hi, CD16-, CCR2+, M2 CD14 + CD16 + CX3CR1+) 203

12.1.3 Toll-Like Receptors 204

12.1.4 Negative Regulation of Toll-Like Receptors 207

12.1.5 Inside Sensors for Outside Pathogens: Nucleotide Oligomerisation Domain-Like Receptors 208

12.1.6 Production of Interleukin 1 210

12.2 Cytokines and the Immune Response 211

12.3 Activation of Macrophages 213

12.3.1 Control of Macrophages 215

12.4 Lipopolysaccharide Stimulation of Macrophages (or Endothelial Cells) 216

12.4.1 Negative Regulators of LPS Activation and TLR Receptor Signalling 217

12.4.2 Interaction IFNγ/TLR Signalling in Macrophages 218

12.5 Dendritic Cells 218

12.6 Signalling by TNFα 220

12.7 Macrophage Migration Inhibitory Factor 222

12.8 Cytokines and Growth Factors 223

12.8.1 Receptors for Cytokines and Cellular Activation 223

12.8.2 IL2Receptor and IL-2 224

12.8.3 Transpresentation of IL-15 226

12.8.4 Negative Regulation of Cytokine Receptors 227

12.9 Connections by Jak-Stats 227

12.10 Activation of Macrophages by IL-1 and TNFα 229

12.11 TRAF Adapter Proteins 229

12.12 CD40 Signalling 231

12.13 Other TNFR Superfamily Molecules 231

12.14 RAGE Receptors and Cytokine Production 232

12.15 IL-10 Immunomodulatory Cytokine 233

12.16 Those Basic Signal Cascades 234

References 236

13 T Lymphocytes 247

13.1 Activation of T Lymphocytes 247

13.1.1 General Scheme of T Lymphocyte Activation 248

13.1.2 Adaptor Proteins 252

13.1.3 CD28 Costimulation 253

13.1.4 NF-κB Activation and T Cell Co-Stimulation* 255

13.2 Control of Lymphocyte Activation by Phosphatases 256

13.3 Downregulation of T Lymphocyte Activation 257

13.3.1 The SLE CD4 T Lymphocyte* 259

13.4 Characteristics of Forms of T Lymphocyte 260

13.4.1 Effector T Lymphocytes 260

13.4.2 CD8 Cytotoxic T Lymphocytes 260

13.4.3 Memory T Cells (CD4 and CD8) 261

13.4.4 Th17 Inflammatory cells 262

13.4.5 T Cell Apoptosis* 262

13.4.6 Anergic CD4 T Cells* 263

13.4.7 Quiescence of T Cells* 266

13.4.8 Suppression of T Cells* 266

13.4.9 T Regulatory Lymphocytes (nTreg, iTreg, Tr-1) 267

13.5 Th1 and Th2 Lymphocytes 268

13.5.1 Interleukin 12 Signalling and Th1 Lymphocytes 270

13.5.2 Regulation of IFNγ Production 271

13.5.3 Th17 Inflammatory Cells 272

13.6 Interleukin 4 and Th2 Lymphocytes 273

13.6.1 Interleukin 13 273

13.7 Respiratory Tract Allergy 274

13.8 Chronic Bronchitis as Obstructive Airway Disease 277

References 277

14 Immunological Controls 293

14.1 Transforming Growth Factor-β Signalling 293

14.1.1 Smad Activity and Other Kinase Pathways* 294

14.1.2 TGFβ and Immune Regulation 296

14.1.3 TGFβ Inhibition of Cell Growth 297

14.1.4 TGFβ and Inhibition of Cell Proliferation 297

14.1.5 TGFβ and Apoptosis 297

14.2 Clinical Implications 298

14.2.1 TGFβ, Connective Tissue Growth Factor, and Fibrosis 298

14.2.2 Connective Tissue Growth Factor 298

14.2.3 Scleroderma 299

14.2.4 TGFβ Is Anti-inflammatory 299

14.3 TGFβ and Cancer 300

14.4 Bone Morphogenetic Proteins* 301

14.5 The Actions of Interferons 301

14.6 Signalling by IFNγ 302

14.7 Signalling by IFNα* 304

14.7.1 Controlling Viruses 305

14.7.2 Plasmacytoid Dendritic Cells 306

14.8 SOCS: Negative Regulation of the Jak-Stat Pathway* 307

14.8.1 Regulation of the Jak-Stat Pathways 309

14.9 Negating Cytokines 309

14.10 Prostaglandin E2 and T Cell Modulation 310

14.11 Interleukin 4 Signalling 310

14.12 Interleukin 13 312

14.13 Decoy Receptors 312

References 313

15 Natural Killer Cells 323

15.1 Receptors for HLA Class I 323

15.1.1 Hyporesponsiveness of NK Cells 325

15.2 ITAMs and NK Cell Receptors 326

15.3 ITIMs and NK Cell Receptors 327

15.4 NK Cells in Action* 328

15.5 Signalling Lymphocyte Activation Molecule and Adapter SAP 330

15.6 NKT Cells* 331

15.7 KIRs and KARs on T Cells* 331

15.8 ILT Molecules on Regulatory Cells 332

References 332

16 B Lymphocytes 337

16.1 B Cell Receptor Signalling 337

16.2 Negative Signalling on B Lymphocytes 340

16.3 CD40 Signalling* 341

16.4 Sustaining B Cells with B Cell-Activating Factor (BLys) 341

16.5 Apoptosis of B Lymphocytes 342

16.6 Control Over B Cell Proliferation* 343

16.7 B Cell Development* 343

16.8 B Cell Tolerance* 345

16.9 Epstein-Barr Virus and B Cell Proliferation* 346

16.10 B Cells of Chronic Lymphatic Leukaemia 347

16.11 The Lymphomas 347

16.12 Plasma Cells in Multiple Myeloma* 348

References 349

17 The Cell Cycle 355

17.1 Control of the Cell Cycle 355

17.2 PI3K and Cell Proliferation* 359

17.2.1 Notch and Cell Proliferation* 359

17.3 Integrins and Cell Proliferation* 359

17.4 C-Myc and Cell Proliferation* 360

17.5 The Cell Cycle and DNA Damage 360

17.6 p53 Tumour Suppressor 362

17.7 Control of the Cell Cycle Checkpoints* 362

17.8 The Cell Cycle of T Lymphocytes* 363

17.9 Liver Regeneration 364

17.10 Tumours and the Cell Cycle 364

17.11 Cell Renewal and Hh Signalling* 365

17.12 Wnt Signalling 366

References 368

18 Cancer 373

18.1 Cancer Cells 373

18.2 Multistage Carcinogenesis in Skin 377

18.3 Breast Cancer 378

18.4 Prostate Cancer 383

18.5 Cadherins and Catenins 385

18.6 Ovarian Cancers 386

18.7 Renal Cancer 388

18.8 Colon Cancer 388

18.9 Epithelial-Mesenchymal Transition 392

18.10 Genes for Metastasis 392

References 394

Index 405