The NPY Family of Peptides in Immune Disorders, Inflammation, Angiogenesis, and Cancer (eBook)

Contents 5
List of contributors 7
Introduction 10
The NPY family of peptides: from neurotransmitters and hormones to immune modulators, cytokines and growth factors 11
Biology of the NPY family of peptides, their receptors and processing enzymes 14
Evolutionary perspective on the NPY-PYY-PP peptides and their receptors 15
Introduction 15
Invertebrate NPY and receptors 17
Vertebrate NPY-family peptides 18
Vertebrate Y receptors 20
Discussion 27
References 32
Function, distribution and molecular pharmacology of NPY- family receptors 41
Introduction 41
Receptors for the NPY family of peptides 44
Signaling pathways of NPY family receptors 47
Distribution of NPY-family receptors 49
Agonists and antagonists for NPY-family receptors 51
Small molecule NPY medicinal chemistry 52
Mutagenesis studies of NPY-family receptors 57
Conclusions and future perspectives 59
References 59
NPY processing in neuronal and non-neuronal tissues by proconvertases 75
Introduction 75
ProNPY proteolysis 75
Structure of convertases 77
What is known about the localization of these enzymes? 77
Heterologous expression of proNPY 78
Coexpression of proNPY with prohormone convertases 79
In vitro proteolytic processing of proNPY 80
NPY and ProNPY presence in tumors, endocrine and non endocrine tissues 81
Processing of ProNPY in PC2 deficient mice 82
Conclusion 83
References 83
Dipeptidyl-peptidase IV and aminopeptidase P: molecular switches of NPY/ PYY receptor affinities 87
Introduction 87
Cell-surface peptidases as peptide-inactivation system 87
Peptidases involved in the degradation of neuropeptide Y (NPY) and peptide YY ( PYY) 89
Aminopeptidases as NPY/PYY convertases 89
Occurrence of proteolytic NPY and PYY fragments 91
Biological importance of aminopeptidase-mediated NPY/PYY conversion 91
Endopeptidases as inactivation enzymes 93
Conclusion and perspectives 94
References 94
The NPY family of peptides in immune disorders and inflammation 97
NPY, NPY receptors and DPPIV in innate immunity and autoimmune disorders 98
Introduction 98
NPY containing nerves and NPY receptors in lymphoid organs 98
NPY receptors in the immune system 100
Dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5, CD26): distribution in the immune system and relevance of the NPY-DPPIV-axis 100
Innate immune function 101
Natural killer cell activity 102
Autoimmunity 106
Autoimmune models of multiple sclerosis (MS): Experimental allergic encephalomyelitis ( EAE) 106
Concluding remarks 110
References 111
NPY and phagocytic cell functions 118
General effects of NPY on macrophages 118
Factors that could be involved in the effect of NPY on macrophage functions 123
References 130
NPY in allergic and respiratory disorders 134
Introduction 134
Functional studies 135
NPY effect on airway mucus secretions 135
NPY receptors 135
Endogenous release of NPY 135
Modulator effects of NPY 136
NPY metabolism 137
NPY and the immune system 138
NPY in airway diseases 138
Conclusion 139
References 139
NPY analgesia: moving from acute to chronic pain 145
Introduction 145
NPY in animal models of acute pain 146
NPY in animal models of chronic inflammatory pain 147
NPY in animal models of neuropathic pain 150
Presynaptic mechanisms of the spinal analgesic actions of NPY 151
References 154
The NPY family of peptides and angiogenesis 159
NPY as a mediator of neurogenic angiogenesis and revascularization of ischemic tissues 160
Introduction 160
Complexity of angiogenesis and arteriogenesis: Can a single growth factor do it? 161
Sympathetic nerves are activated at angiogenic sites 162
NPY is an angiogenic neurotransmitter 162
NPY stimulates angiogenesis 163
and 163
Hindlimb ischemia activates NPY-Y2 receptor system 164
NPY stimulates revascularization of ischemic hindlimb 166
NPY-mediated angiogenesis in tissue growth and regeneration 168
Summary and conclusions 169
References 171
NPY-induced angiogenesis in retinopathy and wound healing 176
Angiogenic activity of NPY 176
NPY receptors and angiogenesis 177
NPY and wound healing 178
NPY and diabetic retinopathy 178
Conclusions 179
References 181
NPY in vascular inflammation, remodeling and atherosclerosis 184
Introduction 184
NPY is a vascular mitogen 185
NPY induces medial hypertrophy and stimulates neointima formation 185
NPY stimulates thrombosis, vascular inflammation and atherosclerosis 186
Stress mimics NPY-induced lesions by activating Y1 receptors 188
Platelet NPY as a risk factor for exaggerated vascular remodeling 189
Neuronal-megakaryocyte interaction contributes to vascular remodeling 190
Summary and conclusions 192
References 193
The NPY family of peptides as growth factors in neurodegenerative diseases and tumor biology 196
NPY as a pleiotropic growth factor 197
Introduction 197
NPY as a vascular growth factor 197
NPY as a neuroproliferative factor 201
NPY in the immune cells 202
Summary 204
References 204
NPY and hippocampal neurogenesis 209
Introduction 209
Development of the granule cell layer of the dentate gyrus 210
Hippocampal neurogenesis 211
NPY and hippocampal neurogenesis 212
NPY control of dentate neurogenesis 222
NPY, neurogenesis and cognitive function 224
NPY, behaviour and mood control 224
Conclusion 225
References 225
NPY family of peptides in neural crest-derived tumors 231
Introduction 231
Neuroblastoma 231
Ewing’s sarcoma family of tumors 236
Pheochromocytoma 238
Summary 240
References 240
NPY family of peptides in endocrine, breast and prostate tumors 245
Introduction 245
NPY family of peptides in endocrine tumors 246
NPY family of peptides in breast tumor 250
NPY family of peptides in prostate tumor 250
Conclusions and perspectives 251
References 252
Summary 257
Future directions and therapeutic perspectives for NPY/PYYbased anti- inflammatory and tumor suppressor drugs 258
Index 261