Advances in TNF Family Research (eBook)

Proceedings of the 12th International TNF Conference, 2009

David Wallach, Andrew Kovalenko, Marc Feldmann (Herausgeber)

eBook Download: PDF

2010 | 2011
XXXVI, 844 Seiten
Springer New York (Verlag)
978-1-4419-6612-4 (ISBN)

Infos

The biennial TNF-family conferences have been held over the past 20 years, from the time that TNF was cloned. These meetings have followed the enormous progress in this field. Much is now known about the members of the TNF ligand and receptor families, their signaling proteins, mechanisms of action and cellular functions. This volume is the proceedings of the 12th TNF International Conference, held in April 2009. This conference focuses on the physiological, pathophysiological, and medical significance of these important regulators. Sessions at the meeting specifically address their involvement in immunity, development, apoptosis, autoimmunity, cancer, and infection, the normal function and pathology of the neuronal system, as well as major unresolved questions about their mechanisms of action.

Inhalt

Preface by David Wallach 4
The Biennial International TNF Conferences and Their Proceedings 4
References 7
Preface by Marc Feldmann 8
Introduction 8
The TNF/TNF-R Family: A Gold Mine for Clinical Therapeutic Targets? 8
Reference 9
Contents 11
Contributors 19
Part I Roles of the TNF Family in Tissue Homeostasis and Normal Development 35
1 Workshop Summary: Roles of the TNF Family in Normal Development and Cancer 36
2 TNF Conference 2009: Beyond Bones RANKL/RANK in the Immune System 38
The Role of the RANKLRANKOPG Axis in Bone Remodeling 38
RANKLRANK Signaling in the Immune System 39
Lymph Node Development 39
RANKL--RANK Signaling in T-Cell--Dendritic Cell Interactions 40
RANKL0RANK Control the Development of AIRE+ Medullary Epithelial Cells 42
RANKL--RANK Signaling in UV-Induced Immunosuppression 44
Functions of RANKL--RANK in Extramedullary Hematopoiesis and B Cells 45
RANKLRANK Signaling, T Cells and Bone Loss The Foundation of Osteoimmunology 46
RANKLRANK Are the Molecular Triggers of Bone Loss in Arthritis 47
RANKL Inhibition as a New Therapy to Control Bone Loss in Human Patients 50
Conclusions 50
References 51
3 The Edar Subfamily in Hair and Exocrine Gland Development 56
Introduction 56
Conservation of the Edar Subfamily 56
Edar Subfamily in Hair Follicle Development 57
Intricate Interplay Between Edar and Wnt Pathways Regulates Hair Development 58
Transcriptional Targets of Edar 59
Functional Redundancy Between Troy and Edar 60
Edar Subfamily in Glandular Appendages 61
Mammary Gland Development 62
Concluding Remarks 63
References 63
4 High Endothelial Venule Reporter Mice to Probe Regulation of Lymph Node Vasculature 67
Introduction 67
Materials and Methods 69
Mice 69
Immunization with Oxazolone 70
Development of HEC6ST-GFP Reporter Mice 70
Immunofluorescence Analysis 71
Results and Discussion 71
Vessels Positive for Markers of both HEVs and LVs Are Apparent After Immunization 71
HEC6ST-eGFP Mice Have Been Developed 72
HEC6ST-eGFP Mice Recapitulate Endogenous HEC6ST Expression 74
References 75
5 Eiger and Wengen: The Drosophila Orthologs of TNF/TNFR 77
Identification and Signaling Mechanisms of Eiger 77
Role of Eiger in Epithelial Tumor Suppression 78
Other Physiological Roles of Eiger 80
Roles in Host Defense 80
Role in Cell Proliferation 81
Role in Pain Sensitization 81
Further Genetic Analysis of Eiger Signaling 81
References 81
Part II Novel Aspects of Signaling Activation by the TNF Family: Novel Aspects of the Functions of the TRAFs and cIAPs 83
6 Workshop Summary: Novel Aspects of the Functions of the TRAFs and cIAPs 84
References 90
7 TRAF2 and Cellular IAPs: A Critical Link in TNFR Family Signaling 93
Discovery of Cellular IAP Proteins and TRAF2 93
Structural Properties of Cellular IAPs and TRAF2 93
TRAF2 and c-IAP Proteins in Signaling Pathways 96
Regulation of Apoptotic Pathways by c-IAPs and TRAF2 99
Targeting c-IAPs and TRAF2 for Therapeutic Intervention 101
References 103
8 New Perspectives in TNF-R1-Induced NF-B Signaling 109
TNF-R1-Induced Activation of Canonical NF-B 109
cIAP1/2 Are Required for RIPK1 Ubiquitylation and NF-B Activation 111
RIPK1 Is Not Required for NF-B Activation 113
Alternative Mechanisms for NF-B Activation 114
NF-B and TNF-Mediated Cell Death 115
References 116
9 Structural Studies of NEMO and TRAF6: Implications in NF-B Activation 119
References 120
Part III Novel Aspects of Signaling Activation by the TNF: Ubiquitin Modification of Signaling Proteins 122
10 Modification by Single Ubiquitin Moieties Rather Than Polyubiquitination Is Sufficient for Proteasomal Processing of the p105 NF-B Precursor 123
Introduction 123
Results 125
Involvement of the Ubiquitin System in Processing of p105 125
Processing of p105 Does Not Require Polyubiquitination 125
Monoubiquitination(s) Is Sufficient for Processing of p105 In Vivo 128
Processing of p105 Requires Multiple Monoubiquitinations 131
The 26S Proteasome Binds Multiply Monoubiquitinated p105 131
Discussion 131
References 134
11 Selective Binding of Linear Ubiquitin Chains to NEMO in NF-kappaB Activation 135
Introduction 135
Main Text 136
The NEMO--UBAN Domain Selectively Binds to Linear Ubiquitin Chains 136
The NEMO--UBAN Domain Forms a-Helical Dimer 137
Determination of Linear-Ubiquitin Binding Surfaces in the NEMO--UBAN Domain 137
Role of Linear Ubiquitin Binding to NEMO in Regulation of Signaling 137
Discussion and Future Perspectives 139
References 141
12 The Linear Ubiquitin Chain Assembly Complex (LUBAC) Forms Part of the TNF-R1 Signalling Complex and Is Required for Effective TNF-Induced Gene Induction and Prevents TNF-Induced Apoptosis 143
Introduction 143
Identification of HOIL-1 and HOIP as Novel Components of the Native TNF-RSC 145
LUBAC Recruitment to the TNF-RSC Is Dependent on TRADD, TRAF2/5, and cIAP1/2 145
HOIL-1 and HOIP Directly Interact with Specific Polyubiquitin Chains 146
HOIL-1 and HOIP Mediate TNF-Induced Signalling Events, Gene Induction, and Protect from TNF-Induced Apoptosis 147
HOIL-1 and HOIP Are Required for Stable TNF-RSC Formation 147
Conclusions 148
References 152
13 Temporal Control of TNF Signaling by Miz1 155
References 156
Part IV Novel aspects of Signaling Activation by the TNF Family: TNF Signaling and Gene Regulatory Networks 157
14 Large-Scale RNAi Screens to Dissect TNF and NF-B Signaling Pathways 158
Introduction 158
TNF-Induced NF-B Activation 159
TNF/NF-B Signaling: A Link Between Inflammation and Cancer 161
RNAi Screens to Dissect Signaling Pathways 162
Design Principles of Large-Scale RNAi Screens for TNF/NF-B 162
New Targets, New Drugs? 164
References 165
15 Pathogenic Role of IL-6 Combined with TNF- or IL-1 in the Induction of Acute Phase Proteins SAA and CRP in Chronic Inflammatory Diseases 167
Introduction 167
Contribution of Cytokines to the Pathogenesis of RA 167
In Vitro SAA Induction Mechanism 168
In Vitro CRP Induction Mechanism 171
Inhibition of SAA and CRP Production by IL-6 Blockade Both In Vitro and In Vivo 172
Pathogenic Role of IL-6 Combined with TNF- or IL-1 on the Induction of SAA and CRP in RA Based on Evidence Obtained from In Vitro Experiments 174
References 175
16 Understanding Life and Death at CD95 177
Introduction 177
Results and Discussion 180
Materials and Methods 184
Cell Lines 184
Antibodies and Reagents 184
Analysis of Total Cellular Lysates 185
NF-B Activation Assay 185
Cell Death Assay 185
References 186
17 Unique Personalities Within the NF-B Family: Distinct Functions for p65 and RelB in the Osteoclast 188
Distinct Kinetics for Activation of p65 and RelB in the OC Lineage 189
Role of p65 in OC Apoptosis 189
Role of RelB in OC Differentiation 190
cRel Is Not Required for Osteoclastogenesis 190
Summary 191
References 192
Part V Roles of the TNF Family in Infectious Diseases and Interrelationship of the TNF Family and Pattern Recognition Receptor Signaling: Roles of the TNF Family in Infectious Diseases 193
18 Workshop Summary: Functions of the TNF Family in Infectious Disease 194
The Role of Soluble TNF, Membrane TNF, and Lymphotoxin in Mycobacterium tuberculosis Infection 194
Interplay Between Heme and TNF in Severe Malaria 195
TNF in Chagas Disease 195
Subversion of TNF-Mediated Viral Control by Poxviruses 195
4-1BB/4-1BBL in Influenza and HIV Infections 196
A Lymphotoxin Pathway to Hepatocellular Carcinoma 196
Emerging Themes 197
References 197
19 Role of 4-1BBL and TRAF1 in the CD8 T Cell Response to Influenza Virus and HIV 199
Introduction 199
Role of TRAF1 in 4-1BB Signaling 199
How Unique Are 4-1BB-Induced Survival Signals? 201
Role of 4-1BBL and TRAF1 in Restoring Function in CD8 T Cells from Chronically HIV Infected Individuals 201
Role of 4-1BBL in Mild Versus Severe Influenza Virus Infection 202
Role of 4-1BBL and TRAF1 in T Cell Memory 203
A Model for the Maintenance of CD8 T Cell Memory 204
Concluding Remarks 205
References 205
20 Roles of Soluble and Membrane TNF and Related Ligands in Mycobacterial Infections: Effects of Selective and Non-selective TNF Inhibitors During Infection 209
Introduction 209
Roles of TNF in Mycobacterial Infections 210
Soluble TNF, Membrane-Bound TNF, and Lymphotoxins 210
Role of TNF in Experimental Animal Models of Tuberculosis Infection 212
Membrane TNF Protects from BCG and Acute Tuberculosis Infections 213
Lymphotoxins and LIGHT in Immunity to Mycobacterial Infections 214
Neutralization of TNF and Risks of New Infection and Reactivation of Latent Tuberculosis 214
Strategies to Block TNF Activities 215
TNF and Chemokines in Mycobacterial Infections 217
Conclusion 217
References 218
21 Poxviral TNFRs: Properties and Role in Viral Pathogenesis 224
Poxviruses 224
Poxviral TNF-Binding Proteins 224
vTNFRs in Pathogenesis 227
Ectromelia Virus 227
Conclusions 229
References 229
22 Heme Sensitization to TNF-Mediated Programmed Cell Death 232
Introduction 232
Malaria 233
A Central Role of Free Heme in the Pathogenesis of Severe Malaria 234
Free Heme Sensitizes Cells to Undergo TNF-Mediated Apoptosis 236
Concluding Remarks 237
References 238
23 TNF- and TNFR in Chagas Disease: From Protective Immunity to Pathogenesis of Chronic Cardiomyopathy 241
Introduction 241
TNF- Polymorphisms in Chagas Disease 242
TNF- in Trypanosoma cruzi Immunity 243
Beneficial Effects of TNF- Blockade in Trypanosoma cruzi Infection 244
Conclusions and Future Avenues 246
References 247
24 Lymphotoxins Link to Carcinogenesis: Friend or Foe? From Lymphoid Neogenesis to Hepatocellular Carcinoma and Prostate Cancer 251
Lymphotoxin: Past and Present 251
From Toxicity to Function 251
Lymphotoxin, Lymphoid Neogenesis, and Lymphoid Microarchitecture 252
Lymphotoxin and Inflammation 253
LTR Signaling in Health and Disease 255
NFB, Chronic Inflammation, and Cancer 255
Lymphotoxin and Its Link to Cancer 257
LTR Signaling in the Liver 258
Hepatic LTR Signaling and Hepatocellular Carcinoma 258
References 264
Part VI Roles of the TNF Family in Infectious Diseases and Interrelationship of the TNF Family and Pattern Recognition Receptor Signaling: Interrelationship of the TNF Family and Pattern Recognition Receptor Signaling 270
25 Anti-inflammatory Functions of Caspase-8 271
Involvement of Signaling Proteins Activated by TNF/NGF Family Members in Signaling Pathways Activated by Other Inducers 271
Inflammatory Processes Triggered by Caspase-8 Deficiency 272
Exploring the Mechanism for a Skin Inflammatory Disease Prompted by Caspase-8 Deficiency in the Epidermis Revealed an Inhibitory Effect of Caspase-8 on Signaling for IRF3 Activation 274
Regulation of RIG-I Signaling by Caspase-8 277
Epilogue 277
References 278
26 Endogenous Ligand-Induced Activation of TLR4 in Pre-metastatic Phase Is Both Downstream and Upstream of TNF Signaling 279
Discovery of Endogenous Ligands for TLR4 in Pre-metastatic Milieu 279
The Complex Paracrine Modes in TNFR and TLR4 Crosstalks 281
Conclusion 283
References 284
Part VII Novel Aspects of Immune Regulation by the TNF Family 287
27 Introductory Words About TL1A/DR3 288
References 290
28 Introductory Words About TWEAK/Fn14 292
References 294
29 Insights into TL1A and IBD Pathogenesis 295
Introduction 295
TL1A (TNFSF15) Is an IBD Severity Associated Gene 296
Upstream Regulators of the TL1A-DR3 Signaling Pathway 297
Downstream Effects of the TL1A-DR3 Signaling Pathway 300
Role of TL1A in Inflammatory Diseases 301
Conclusion 302
References 302
30 The Role of TNFRSF25:TNFSF15 in Disease and Health? 305
Introduction 305
Structure, Expression and Signaling 306
TL1A:TNFR25 in T Cell Function 308
TL1A:TNFR25 in Auto-aggressive Disease 309
TL1A:TNFR25 in Health? 311
References 311
31 Identification of New Candidates as Mucosal Vaccine Adjuvant in TNF Family Cytokines 315
Mucosal Immunity and Vaccine 315
Identification of New Candidate Mucosal Vaccine Adjuvants Among TNF Superfamily Cytokines 316
Concluding Remarks 319
References 320
32 The TWEAK/Fn14 Pathway in Tissue Remodeling: For Better or for Worse 321
Introduction 321
TWEAK 323
Fn14 323
Fn14 Signaling 324
Role of TWEAK/Fn14 Pathway in Disease 326
Role of TWEAK/Fn14 in Intestinal Inflammation and Injury 332
Summary and Perspective 335
References 336
33 TWEAK and the Kidney: the Dual Role of a Multifunctional Cytokine 339
Introduction 339
TWEAK and Fn14 Expression in Renal Cells 340
TWEAK Biological Activity in the Kidney 341
Pro-inflammatory Effect of TWEAK in the Kidney 341
TWEAK and Renal Cell Death 341
TWEAK and Renal Cell Proliferation 342
TWEAK and Fn14 in Experimental Kidney Disease 343
Acute Kidney Injury 343
Non-inflammatory Renal Regeneration Model: Uninephrectomy 345
Autoimmune Kidney Disease: Lupus Nephritis 346
Future Lines of Research 346
References 347
34 TWEAK and TNF Regulation of Sclerostin: A Novel Pathway for the Regulation of Bone Remodelling 352
Introduction 352
TWEAK 352
A Role for TNF Family Members in Bone Remodeling 353
Human Osteoblasts and Osteoblast-Like Cell Lines Express Fn14 and TWEAK 353
TWEAK Inhibits In Vitro Mineralisation and Antagonizes the Osteogenic Effect of TNF 353
Effect of TWEAK and TNF on Osteoblast Proliferation 354
Effect of TWEAK and TNF on Osteoblast Osteogenic Gene Transcription 355
Interaction Between TWEAK and TNF 357
The Wnt Signalling Pathway and Inhibitors: Sclerostin 357
TWEAK Alone and in Combination with TNF Induce Sclerostin Expression 357
Concluding Remarks 358
References 360
Part VIII Control of Lymphocyte Function and Repertoire by the TNF Family 364
35 Workshop Summary: Control of Lymphocyte Function and Repertoire by the TNF Superfamily 365
36 The Canonical and Unconventional Ligands of the Herpesvirus Entry Mediator 367
Introduction 367
Canonical Ligands: LIGHT and LT 369
Unconventional Ligands: BTLA and CD160 370
Distinct Ligand Binding Sites on HVEM 371
Viral Ligands of HVEM and BTLA: HSV gD and UL144 371
The Trans and Cis of HVEM Signaling 372
References 373
37 The Lymphotoxin Pathway as a Novel Regulator of Dendritic Cell Function 377
References 384
38 Involvement of the Cytokine Receptor CD137 in Murine Hematopoiesis 389
Introduction 389
Effects of CD137 on Murine Hematopoietic Progenitor Cells 390
CD137 and Its Ligand Are Expressed in the Bone Marrow 390
CD137 Induces Proliferation and Colony Formation of Hematopoietic Progenitor Cells 390
CD137 Induces Cell Differentiation Toward Macrophages 392
Other Activities of CD137 in Hematopoiesis 393
Conclusion 394
References 395
39 LTBR-Pathway in Sjogrens Syndrome: CXCL13 Levels and B-cell-Enriched Ectopic Lymphoid Aggregates in NOD Mouse Lacrimal Glands Are Dependent on LTBR 397
The TNF Family and Inflammatory Versus Homeostatic Pathways 397
Ectopic Lymphoid Tissue Development and Homeostasis in Disease 397
What Is the Role of Ectopic Follicles in Disease 398
Clinical Utility of Dispersing Ectopic Follicles in Sjogrens Syndrome 398
Role of LTBR in Lymphocytic Infiltrates in Lacrimal Glands 399
Involvement of the LTBR Axis in Lacrimal Gland Pathology 400
Affymetrix Chip Analysis Implication of LTBR Pathway and Chemokine CXCL13 400
CXCL13 Production in Lacrimal Glands Lacking FDC Networks 402
References 403
40 MEK Kinase 1: Kinase Domain Deficiency in Mice Reveals a Role in Orchestrating the Thymus-Dependent Immunity and TNFR Family Signaling 405
Introduction 405
Activation of E3 Ub Ligase Itch by the T-Cell Receptor 406
Thymus-Dependent Immune Responses and TNFR Signaling in B Cells 407
Two-Stage Cytokine Receptor Signaling 408
Perspectives 409
References 410
Part IX Advances in Applying Our Knowledge to Therapy: Mechanisms of Pathological and Therapeutic Effects of the TNF Family 412
41 Introduction to the Session Mechanisms of Pathological and Therapeutic Effects of the TNF Family 413
42 Mechanisms Regulating TNF-Driven Gut and Joint Inflammation 415
The Gut Joint Axis in Spondyloarthritis 415
Modeling Spondyloarthritis in Mice: Which Cells Are Targets of Pathogenic TNF? 416
NKT Cells: Regulators or Effectors in Arthritic Disease? 417
References 419
43 Lessons from Anti-TNF Biologics: Infliximab Failure in a TRAPS Family with the T50M Mutation in TNFRSF1A 421
Assessment of the Effect of Anti-TNF Biologicals in an Irish Family with the T50M Variant of TNFRSF1A 422
Therapeutic Options in the Treatment of TRAPS: A Revised View 425
Conclusion 428
References 429
44 Modalities of Experimental TNF Blockade In Vivo: Mouse Models 432
Introduction 432
Results and Discussion 433
Novel Humanized Mice for Studying TNF Inhibition In Vivo 433
Mouse Models to Evaluate Functions of TNF Produced by Distinct Cell Types or in Distinct Molecular Forms (or Both) 436
Distinct Functions of TNF Produced by Individual Types of Immunocytes in Disease 436
Effects of Non-conventional TNF Blockers on Acute Septic Shock and on the Structure of Secondary Lymphoid Organs 439
References 440
45 Tumor Necrosis Factor- Signaling via TNFR1/p55 Is Deleterious Whereas TNFR2/p75 Signaling Is Protective in Adult Infarct Myocardium 443
Background 443
Aging and Angiogenesis 443
TNF, TNF Receptors, and Angiogenesis 443
Aging, TNF Signaling, and Post-ischemic Recovery 444
Results 445
Constitutive Expression of p75 Is Decreased in Human PB EPCs from Donors of Increasing Age 445
Post-AMI Survival and Functional Myocardial Recovery Is Impaired in Old p75KO Mice 445
Cardiac Troponin I (cTnI) Expression Is Increased in Infarct Border Zone in p75KO Mice 448
Capillary Density Is Decreased in Infarct and Infarct Border Zone in Old WT and Young and Old p75KO Mice 449
Compared to Old WT Mice Post-AMI Functional Capillary Density Is Decreased in Old p75KOs in Infarct Border Zone 449
Ischemia-Induced Apoptosis Is Increased in the Myocardium of Old p75KO Mice 28 Days Post-AMI 451
Expression of Several Angiogenic Growth and Stem Cell-Derived Factors and Their Receptors Is Decreased in Peripheral Blood EPCs from Adult Donors 451
Summary 454
References 456
46 TNF- Regulation of CD38 Expression in Human Airway Smooth Muscle: Role of MAP Kinases and NF-B 459
Introduction 459
CD38/cADPR Signaling Pathway 459
Regulation of CD38 Expression in ASM Cells 461
Cd38 Gene and Promoter 461
Cytokine Regulation of CD38 Expression 463
TNF- and CD38 Expression 463
TNF- 463
TNF- Signaling and MAP Kinases 464
Concluding Remarks 466
References 466
47 Functional Consequences of Disease-Associated Mutations in TNFR1 Elucidated by Transcriptome Analysis 470
Introduction 470
TNFR1 Mutations and TRAPS 471
Clinical Features 472
Dissecting the Molecular Pathogenesis of TRAPS 472
Altered Gene Expression Profile in Cells Expressing TNFR1 TRAPS Mutants 474
References 476
48 Tumor Necrosis Factor- and Kidney Function: Experimental Findings in Mice 480
Direct Effects of TNF- on Renal Hemodynamics and Excretory Function 481
What Would Be the Mechanism (s) of These Renal Actions TNF-? 481
What Would Be the Mechanism of Natriuresis Induced by TNF- ? 483
Renal mRNA Expression of Oxidative and Nitrosative Enzymes in Response to TNF Infusion 485
Conclusion 486
References 487
49 Strategies to Inhibit the Toxicity of Systemic TNF Treatment 490
Introduction 490
Inhibition of Matrix Metalloproteinases 491
Induction of HSP70 491
Inhibition of Cytokines 492
Conclusion 492
References 492
Part X Advances in Applying our Knowledge to Therapy: Rational Design of New Means for Therapeutic Modulation of Function of the TNF Family 494
50 Workshop Summary: Introduction to Rational Design of New Means for Therapeutic Modulation of Function of the TNF Family 495
References 498
51 Anti-inflammatory Effects of a Novel TNFR1-Selective Antagonistic TNF Mutant on Established Murine Collagen-Induced Arthritis 500
Anti-TNF Therapy for Autoimmune Diseases 500
Creating Functional Mutants with Advanced Medical Applications 501
Bioconjugation as a Polymeric DDS 503
Conclusion Remarks 505
References 505
52 A Proliferation-Inducing Ligand (APRIL): The Development of Antagonistic Agents as Potential Therapeutics and Deciphering the Role of Heparan Sulphate Proteoglycans (HSPGs) in APRIL Signalling 508
Introduction 508
The Development and Characterisation of Antagonistic Monoclonal Antibodies Against Human APRIL 509
The Role of HSPGs in APRIL Signalling 510
References 512
53 Genetic Engineering of Death Ligands for Improvement of Therapeutic Activity 514
Introduction 514
Stabilization of Trimer Formation 516
Conversion of Inactive Death Ligands into Highly Active Molecules Through Tumor-Directed Targeting 517
Targeting-Dependent Enhancement of TRAILs Antitumoral Activity 518
Exploiting Therapeutic Potential of CD95L- and TNF-Based Reagents: Targeted Activation and Prodrugs 520
Bifunctional Death Ligand Fusion Proteins 523
Conclusion 524
References 525
54 Computational Design of TNF Ligand-Based Protein Therapeutics 527
Concluding Remarks 535
References 536
Part XI Roles of the TNF Family in Neuronal Development, Function, and Pathology 541
55 Workshop Summary: Roles of the TNF Family in Neuronal Development, Function and Pathology 542
56 TNF: A Key Neuroinflammatory Mediator of Neurotoxicity and Neurodegeneration in Models of Parkinson's Disease 544
References 545
57 The Contribution of TNF to Synaptic Plasticity and Nervous System Function 546
References 558
58 Intracellular and Intercellular Cross Talk Between NGF and TNF 563
Introduction 563
TNF Signalling Through TNFR2 Modulates NGF Signalling 563
NGF Appears to Change the Effects of Endogenous TNF on Neuronal Survival 564
Possible Contributions of Endogenous TNF to Tumourigenesis of Neuroblastomas 565
Where Is the Endogenous Source of NGF in the Adult Nervous System? 565
A Possible Intercellular Loop of NGF and TNF Expression 566
Conclusion 566
References 567
59 TNFR2 Target for Therapeutics Against Neurodegenerative Diseases? 570
TNF and Its Receptors 570
TNF and TNFRs in Neurodegenerative Disease 570
TNF and SK Channels 573
Statins and the TNFR2 Neuroprotective Pathway 574
Overall Discussion and Conclusion with Future Perspectives 575
References 575
60 A Role for Neuronal NF-B in Suppressing Neuroinflammation and Promoting Neuroprotection in the CNS 577
Introduction 577
Transcription Factor NF-B in EAE Pathology 577
Conditional Gene Targeting of IKK Kinase During Autoimmune, Demyelinating Disease 578
Proinflammatory and Neuroprotective Effects During EAE in nIKKKO Mice 580
Conclusion 582
References 582
Part XII Cell Death Mechanisms Controlled by the TNF Family 584
61 Workshop Summary: Cell Death Mechanisms Controlled by the TNF Family 585
Introduction 585
62 A RNA Interference Screen Identifies RIP3 as an Essential Inducer of TNF-Induced Programmed Necrosis 589
Introduction 589
Identification of RIP Kinases as Critical Mediators for Programmed Necrosis 589
RIP3 Is Recruited to the Cytoplasmic Signaling Complex and Interacts with RIP1 via the RHIM 590
The RHIM and Kinase Domains of RIP1 and RIP3 Are Essential for Programmed Necrosis 590
RIP3 Controls ROS Production 591
The Role of RIP3 in T-Cell Death 591
RIP3 Participates in Anti-viral Innate Immune Responses 592
References 593
63 The Extracellular Matrix Protein CCN1 Dictates TNF and FasL Cytotoxicity In Vivo 594
Introduction 594
The CCN Family of Extracellular Matrix Proteins 594
CCN Proteins and TNF Cytokines Synergize to Induce Apoptosis In Vitro and In Vivo 595
ROS Mediates Signaling Cross Talk Between CCNs and TNF or FasL 598
Future Prospects 599
References 599
64 Compartmentalization of TNF-Receptor 1 Signaling: TNF-R1-Associated Caspase-8 Mediates Activation of Acid Sphingomyelinase in Late Endosomes 603
TNF-Receptor Signaling 603
Non-apoptotic Signaling of TNF-Receptor 1 603
Apoptosis-Inducing Signals from TNF-Receptor 1 604
Mechanisms of Receptor Internalization 604
DISC Assembly Occurs on Internalized TNF-Receptosomes 605
A-SMase Activation by TNF 608
Caspase-8 Deficiency Prevents TNF Activation of A-SMase and Cathepsin D 609
Active Caspase-8 Colocalizes with Internalized TNF-Receptosomes and A-SMase 609
Proteolytic Cleavage of Pro-A-SMase Correlates with Enhanced Enzymatic Activity 610
References 611
65 TNF/TNF Receptor 1-Mediated Apoptosis in Hepatocytes 615
Introduction 615
The Biology of TNF and TNF Receptor 1 System in the Liver 616
The Signaling and Function of TNF Receptor 1 in the Liver 617
Other Unique Observations on TNFR1 in Hepatocytes 619
References 620
66 Regulation of Cell Death by c-FLIP Phosphorylation 623
Introduction 623
Activation of Apoptosis by Death Receptors 623
c-FLIP as a Regulator of the Cell Fate 624
Regulation of c-FLIP by Post-Translational Modifications 625
PKC-Mediated Phosphorylation Regulates the Stability of the Short c-FLIP Isoforms 626
Pursuing Interest on c-FLIP Ubiquitylation 627
References 627
Appendix I: Contributors to Abstracts of Talks and Posters at the 12th TNF Conference 629
Appendix II: Abstracts of Talks and Posters Presented at the 12th TNF Conference 640
KEYNOTE LECTURE 640
ORCHESTRATION OF THE TNF RESPONSE BY MESSENGER RNA STABILITY AND MICRORNAS 640
LECTURES ROLES OF THE TNF FAMILY IN TISSUE HOMEOSTASIS AND NORMAL DEVELOPMENT 641
BEYOND BONES - THE MULTIPLE FUNCTIONS OF RANKL-RANK 641
HAIR FOLLICLE RANK-LIGAND REGULATES EPITHELIAL GROWTH VIA BCL-3 641
TNFs IN HAIR AND MAMMARY GLAND DEVELOPMENT 642
TNF PRIMES ENDOTHELIAL CELLS FOR ANGIOGENIC SPROUTING BY INDUCING A TIP CELL PHENOTYPE 643
LTalpha CONTRIBUTES TO LYMPHATIC VESSEL DEVELOPMENT AND FUNCTION 643
TNF SIGNALING AND ITS PHYSIOLOGICAL ROLES IN DROSOPHILA 644
ROLES OF THE TNF FAMILY IN CANCER 644
THE EGFR PATHWAY: RECENT LESSONS IN SIGNAL TRANSDUCTION 644
STUDY OF APRIL EXPRESSION AND APRIL-MEDIATED SIGNALING IN BREAST CANCER 645
ROLE OF RECEPTOR ACTIVATOR OF NF-B LIGAND (RANKL) IN TUMORIGENESIS AND METASTASIS 646
TNF-MEDIATED MYELOID CELLS SURVIVAL IS NECESSARY FOR TUMOR GROWTH 648
FAS SIGNAL PROMOTES LUNG CANCER GROWTH BY RECRUITING MYELOID-DERIVED SUPPRESSOR CELLS VIA CANCER CELL-DERIVED PGE2 648
NF-KAPPAB INHIBITION AND SKIN CANCER: A VISCOUS CIRCLE OF CHRONIC INFLAMMATION AND IMMUNOSUPPRESSION DRIVEN BY TNFR1 IN KERTINOCYTES 649
ENDOGENOUS LIGAND-INDUCED ACTIVATION OF TLR4 IN PRE-METASTATIC PHASE IS BOTH DOWNSTREAM AND UPSTREAM OF TNF SIGNALING 650
MECHANISMS OF THE TUMOR-PROMOTING ACTION OF TNF- IN EPITHELIAL TUMORS 650
NOVEL ASPECTS OF SIGNALING ACTIVATION BY THE TNF FAMILY 651
NON-CANONICAL MODES OF UBIQUITINATION IN REGULATION OF TRANSCRIPTION: PROCESSING OF THE NF- B p105 AND ACTIVATION OF POLYCOMB REPRESSIVE COMPLEX 1 651
SIGNALING LESSONS FROM DEATH RECEPTORS 652
IN VIVO STUDY OF THE (PATHO)PHYSIOLOGICAL ROLE OF THE ANTI-APOPTOTIC AND ANTI-INFLAMMATORY PROTEIN A20, USING GENETICALLY MODIFIED MICE 653
REGULATION OF TNF-INDUCED JNK ACTIVATION AND INFLAMMATION BY SMOR1 654
CULLIN3-BASED POLYUBIQUITINATION AND P62-DEPENDENT AGGREGATION OF CASPASE-8 MEDIATE CELL EXTRINSIC APOPTOSIS SIGNALING 654
SELECTIVE BINDING OF LINEAR UBIQUITIN CHAINS TO NEMO (NF-B ESSENTIAL MODULATOR) IN NF-B ACTIVATION 655
A NOVEL UBIQUITIN LIGASE RECRUITED TO THE TNF-R1 SIGNALLING COMPLEX IS REQUIRED FOR EFFICIENT TNF-INDUCED NF-B ACTIVATION AND GENE INDUCTION 656
TRANSCRIPTIONAL NETWORKS AND SYSTEMS BIOLOGY 657
CHARACTERIZATION OF NOVEL TNF/NF-B SIGNALING PATHWAY COMPONENTS BY GENOME-WIDE RNAI 657
RNA-INTERFERENCE BASED SCREEN IDENTIFIES NEW FACTORS IMPORTANT FOR NF-kappaB ACTIVATION AND TERMINATION 657
CASEIN KINASE 1, NF-B, AND HUMAN LYMPHOMA CELL SURVIVAL 658
PATHOGENIC ROLE OF IL-6 WITH TNF- or IL-1 ON THE INDUCTION OF ACUTE PHASE PROTEINS IN CHRONIC INFLAMMATORY STATUS OF AUTOIMMUNE DISEASE 659
NEW INSIGHTS IN LTBR-MEDIATED NF-B ACTIVATION 659
THE NF-B SIGNALING SYSTEM AS AN INTEGRATOR OF DIVERSE SIGNALS 660
MATHEMATICAL MODELING OF THE TNF-a SIGNALING PATHWAY 660
DYNAMICS WITHIN THE CD95 DEATH-INDUCING SIGNALING COMPLEX DECIDE LIFE AND DEATH OF CELLS 661
TNF- SENSITIZES PRIMARY MOUSE HEPATOCYTES TO FAS/CD95-INDUCED APOPTOSIS: A SYSTEMS BIOLOGY APPROACH 662
UNIQUE PERSONALITIES WITHIN THE NF-B FAMILY: DISTINCT FUNCTIONS FOR P65 AND RELB IN THE OSTEOCLAST 662
THE INTERRELATIONSHIP BETWEEN NF-kappaB, Nrf2 AND KEAP1 IN CONTROLLING TNF INDUCED INFLAMMATORY RESPONSES 663
AATF IS A NOVEL ACTIVATOR OF THE C-JUN TRANSCRIPTION FACTOR UPON UV-LIGHT EXPOSURE 664
MICRORNA miR-146 IS A KEY REGULATOR OF AUTOIMMUNITY AND INFLAMMATION 665
MicroRNA-146a PROTECTS FROM TNF-INDUCED APOPTOSIS 666
miRNA REGULATION OF ENDOTHELIAL CELL RESPONSES TO TNF 666
ROLES OF THE TNF FAMILY IN INFECTIOUS DISEASES AND INTERRELATIONSHIP OF THE TNF FAMILY AND PATTERN RECOGNITION RECEPTOR SIGNALING 667
THE IL-1 RECEPTOR / TOLL-LIKE RECEPTOR SUPERFAMILY: 10 YEARS OF PROGRESS 667
ACTIVATION OF INNATE IMMUNE REACTION BY MAMMALIAN DNA THAT ESCAPED FROM DEGRADATION, LEADING TO ANEMIA AND ARTHRITIS 668
MALARIAL HEMOZOIN IS A Nalp3 INFLAMMASOME ACTIVATING DANGER SIGNAL 669
CASPASE-8 REGULATES CELLULAR RESPONSE TO PATTERN RECOGNITION RECEPTORS 669
CELL-AUTONOMOUS ROLE OF TNFR AND TLR SIGNALING PATHWAYS IN ANTI-BACTERIAL IMMUNITY 670
BEYOND TNFR SIGNALING: THE MULTIFUNCTIONALITY OF TRADD 671
THE FUNCTION OF TRADD IN SIGNALING THROUGH TUMOR NECROSIS FACTOR RECEPTOR 1 AND TRIF-DEPENDENT TOLL-LIKE RECEPTORS 672
ROLE OF 4-1BB AND RELATED TNFR FAMILY MEMBERS IN CD8 T CELL RESPONSES TO VIRUSES 672
CRITICAL ROLE OF MEMBERS OF TNF OF MYCOBACTERIAL INFECTION REACTIVATION OF INFECTION BY TNF INHIBITORS 673
TUMOUR N ECROSI FACTOR ALPHA PRODUCED BY MACROPHAGES AND NEUTROPHILS IS REQUIRED FOR INITIAL PULMONARY PROTECTIVE INNATE IMMUNE RESPONSES BUT IS DISPENSABLE FOR PROTECTIVE IMMUNITY DURING PERSISTENT M. tuberculosis INFECTION 674
A CRITICAL ROLE OF THE POXVIRUS CrmD PROTEIN, A TNF AND CHEMOKINE BINDING PROTEIN, IN IMMUNE EVASION AND PATHOGENESIS 675
HEME SENSITIZATION TO TNF-MEDIATED PROGRAMMED CELL DEATH DICTATES THE OUTCOME OF PLASMODIUM INFECTION IN MICE 676
TNF/TNFR1 SIGNALING UP-REGULATES CCR5 EXPRESSION ON CD8+ T LYMPHOCYTES AND PROMOTES HEART TISSUE DAMAGE IN TRYPANOSOMA CRUZI INFECTION: BENEFICIAL EFFECTS OF TNF BLOCKADE 677
A LYMPHOTOXIN-DRIVEN PATHWAY TO HEPATOCELLULAR CARCINOMA 678
NOVEL ASPECTS OF IMMUNE REGULATION BY THE TNF FAMILY 678
TL1A (TNFSF15): A MASTER REGULATOR OF MUCOSAL INFLAMMATION 678
TL1A-DR3 INTERACTIONS IN T-CELL MEDIATED AUTOIMMUNITY 680
TNFR25/TL1A CONTROL CD4 REGULATORY CELLS, TH17/TH2 POLARIZATION AND NKT-IL-13 ACTIVITY IMPORTANT IN MUCOSAL AND SYSTEMIC IMMUNITY 681
IDENTIFICATION OF NEW CANDIDATES AS MUCOSAL VACCINE ADJUVANT IN TNF SUPERFAMILY CYTOKINES 682
ROLE OF TWEAK/Fn14 PATHWAY IN INTESTINAL INFLAMMATION AND TISSUE REPAIR 683
TWEAK INDUCES PROLIFERATION IN RENAL TUBULAR EPITHELIUM: A ROLE IN RENAL HYPERPLASIA 684
THE EFFECTS OF TWEAK AND TNF ON HUMAN OSTEOBLASTS: MAPK DEPENDENT INDUCTION OF SCLEROSTIN EXPRESSION 685
TWEAK REGULATES PROINFLAMMATORY TNF RECEPTOR-1 SIGNALING 686
Fn14: A COMMON STRUCTURAL FRAMEWORK FOR SPECIES SEQUENCE DIVERGENCE 686
CONTROL OF LYMPHOCYTE FUNCTION AND REPERTOIRE BY THE TNF FAMILY 687
UNCONVENTIONAL LIGAND ACTIVATION OF HVEM MEDIATES CELL SURVIVAL 687
LYMPHOTOXIN-0 RECEPTOR SIGNALING LICENSES DENDRITIC CELLS TO PRIME CD8+ T CELL RESPONSES 688
THE TNF-FAMILY RECEPTORS RANK AND CD40 COOPERATIVELY REGULATE CENTRAL TOLERANCE IN THYMUS 688
THE DUAL ROLE OF TNF ON T CELL ACTIVATION 689
THE ROLE OF CD40 T CELLS IN AUTOIMMUNE DIABETES: THE IDENTIFICATION OF AUTOAGGRESSIVE T CELLS AND A MECHANISM TO THWART PERIPHERAL TOLERANCE 690
APRIL RESTORES B CELL SURVIVAL AND LPS ANTIBODY RESPONSE IN BTK-DEFICIENT MICE 691
REGULATION OF HEMATOPOIESIS BY CD137 692
THE LTR-PATHWAY PROMOTES B-CELL ACCUMULATION LARGELY VIA CXCL-13 EXPRESSION IN ECTOPIC LYMPHOID AGGREGATES IN NOD MOUSE LACRIMAL GLANDS 692
DIFFERENTIAL REQUIREMENT OF LTBR DURING THE MATURATION OF LYMPH NODE ANLAGEN STROMA 693
ANALYSIS OF B LYMPHOCYTE TUMOR NECROSIS FAMILY MEMBER SIGNALLING UTILIZING MEKK1KD TRANSGENIC MICE 694
NOVEL ASPECTS OF THE FUNCTIONS OF THE TRAFS AND CIAPS 694
PROTEIN UBIQUITINATION CASCADES AND SIGNALING BY TNF AND TOLL RECEPTORS 694
A SIGNALING PATHWAY FROM TNF RECEPTOR TO CELL DEATH 695
CRYSTAL STRUCTURE OF TRAF6 REVEALS SPECIFICITY AND MECHANISM OF TRAF6-MEDIATED UBIQUITINATION 696
TRAF2 BALANCES THE LEVELS OF cIAP1 AND cIAP2 THEREBY PROTECTING CANCER CELLS FROM TNF INDUCED CELL DEATH 697
TUMOR NECROSIS FACTOR (TNF) RECEPTOR-ASSOCIATED FACTOR 1 (TRAF1) ENHANCES PROINFLAMMATORY TNF RECEPTOR-2 (TNFR2) SIGNALING AND MODIFIES TNFR1-TNFR2 COOPERATION 698
CELLULAR INHIBITORS OF APOPTOSIS (c-IAPs) ARE CRITICAL REGULATORS OF TNF FAMILY MEDIATED SIGNALING 699
THE cIAP1 AND cIAP2 INTERACTING DOMAIN OF TRAF2 IS IMPORTANT FOR TNF AND TWEAK INDUCED NF-B AND PROTECTION AGAINST TNF INDUCED APOPTOSIS 699
ADVANCES IN APPLYING OUR KNOWLEDGE TO THERAPY 700
AN UPDATE ON LESSONS LEARNED FROM ANTI-TNF THERAPY OF RHEUMATOID ARTHRITIS 700
BLOCKADE OF THE LYMPHOTOXIN-LIGHT PATHWAY AND THE TREATMENT OF AUTOIMMUNE DISEASE 701
EXPLORATION OF THE ROLES OF SOLUBLE AND TRANSMEMBRANE TNF IN ANIMAL MODELS OF INFLAMMATION AND IMMUNITY: COMPARATIVE STUDIES OF SELECTIVE INHIBITORS OF SOLUBLE TNF TO NONSELECTIVE ANTI-TNF BIOLOGICS 702
MECHANISMS OF PATHOLOGICAL THERAPEUTIC EFFECTSOF THE TNF FAMILY 703
TNF DRIVEN ACTIVATION OF INVARIANT NKT CELLS REGULATES COMBINED GUT AND JOINT INFLAMMATION 703
TNF PRIMING OF TYPE I IFN RESPONSES IN MONOCYTES AND MACROPHAGES 704
THE ANTI-TNF DRUG, INFLIXIMAB, HAS A PROINFLAMMATORY ACTION IN PATIENTS WITH TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED PERIODIC SYNDROME (TRAPS) 705
SCIENCE OF TNF BLOCKADE IN VIVO 706
TNF-INDUCIBLE INHIBITOR I-KAPPAB EPSILON MODULATES IL-2 EXPRESSION IN T CELLS THROUGH REGULATION OF C-REL: IMPLICATIONS FOR CHRONIC INFLAMMATORY DISEASE 707
TUMOR NECROSIS FACTOR-A P75 RECEPTOR IS REQUIRED IN POST-MI RECOVERY IN ADULT HEART 708
TNF-ALPHA REGULATION OF CD38 EXPRESSION IN HUMAN AIRWAY SMOOTH MUSCLE: ROLE OF MAP KINASES AND NF-KAPPA B. 709
FUNCTIONAL CONSEQUENCES OF DISEASE-ASSOCIATED MUTATIONS IN TNFR1 ELUCIDATED BY TRANSCRIPTOME ANALYSIS 710
THE ROLE OF TNF SIGNALING IN SPONTANEOUS COLITIS DEVELOPMENT IN MICE LACKING NEMO SPECIFICALLY IN INTESTINAL EPITHELIAL CELLS 711
EFFECTS OF TNF- ON RENAL HEMODYNAMICS AND EXCRETORY FUNCTION IN MICE 712
LIPOPOLYSACCHARIDE PLUS GALACTOSAMINE-INDUCED FATAL HEPATITIS MEDIATED BY SECRETED TNF REQUIRES CASPASE-8 AND THE TWO BH3-ONLY PROTEINS BID AND BIM 713
STRATEGIES TO INHIBIT THE TOXICITY OF SYSTEMIC TNF TREATMENT WITH RETENTION OF ITS ANTITUMOR EFFECT 714
RATIONAL DESIGN OF NEW MEANS FOR THERAPEUTIC MODULATION OF FUNCTION OF THE TNF FAMILY 715
THE STALK REGION OF THE TNF RECEPTORS HIGHLY DETERMINES SOLUBLE TNF RESPONSIVENESS 715
THE EFFECT OF THERAPEUTIC ANTI-TNF AGENTS ON REVERSE SIGNALING VIA MEMBRANE TNF 716
DETERMINANTS FOR PRODOMAIN INHIBITION OF THE TNF- CONVERTING ENZYME (TACE) ZYMOGEN STATE 716
CREATION OF MUTANT LYMPHOTOXIN-ALPHAS WITH ENHANCED BIOACTIVITIES BY PHAGE DISPLAY TECHNIQUE 717
PHARMACOLOGICAL INHIBITION OF Tpl2 KINASE BLOCKS TNFalpha PRODUCTION IN HUMAN MONOCYTES AND MAY REPRESENT A NOVEL TREATMENT FOR RHEUMATOID ARTHRITIS 718
THE DISCOVERY OF A SERIES OF NOVEL SMALL MOLECULE MACROCYCLIC TNF ANTAGONISTS 719
BIOLOGICAL ACTIVITY OF ECTODYSPLASIN A IS CONDITIONED BY ITS COLLAGEN AND HEPARAN SULFATE PROTEOGLYCAN-BINDING DOMAINS 719
NOVEL MECHANISM OF ACTION FOR ANTI-LYMPHOTOXIN-ALPHA IN AUTOIMMUNE DISEASE: DEPLETION OF TH1 AND TH17 CELLS 720
THE DEVELOPMENT AND CHARACTERIZATION OF APRIL ANTAGONISTIC AGENTS 720
Fn14-TRAIL, A CHIMERIC INTERCELLULAR SIGNAL EXCHANGER, ATTENUATES EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 721
NOVEL TRAIL VARIANTS FOR TARGETED CANCER THERAPY 722
DESIGNED RECEPTOR SPECIFIC RHTRAIL VARIANTS ENHANCE INDUCTION OF APOPTOSIS IN CANCER CELLS 723
APOMAB, A FULLY HUMAN AGONISTIC DR5 MONOCLONAL ANTIBODY INHIBITS TUMOUR GROWTH AND OSTEOLYSIS IN MURINE MODELS OF BREAST CANCER DEVELOPMENT AND PROGRESSION 724
ROLES OF THE TNF FAMILY IN NEURONAL DEVELOPMENT, FUNCTION PATHOLOGY 725
CENTRAL AND SYSTEMIC ACTION OF CYTOKINES IN NEURODEGENERATION 725
In vivo AND in vitro VALIDATION OF TNF AS A KEY NEUROINFLAMMATORY MEDIATOR OF NEUROTOXICITY AND NEURODEGENERATION IN MODELS OF PARKINSON'S DISEASE 726
THE CONTRIBUTION OF TNF TO SYNAPTIC PLASTICITY AND NERVOUS SYSTEM FUNCTION 727
AXONAL SELF-DESTRUCTION AND NEURODEGENERATIVE DISEASE 727
TNFalpha CHANGES DOWNSTREAM PATHWAYS OF NGF SIGNALLING FROM Erk1/2 TO Akt, WHICH BLOCKS NGF-DEPENDENT DIFFERENTIATION OF NEUROBLASTOMA CELLS 728
TNF RECEPTOR 2 SIGNALING: A TARGET FOR THERAPEUTIC INTERVENTIONS AGAINST NEURODEGENERATIVE DISEASES? 729
CASPASE 8 MEDIATES NEURON DEATH FOLLOWING in vivo AND in vitro EXCITOTOXIC INJURY 729
THE DEATH RECEPTOR ANTAGONIST C-FLIP IS NECESSARY FOR NEURONAL DIFFERENTIATION MEDIATED BY NEUROTROPHINS 730
NEURONAL NF-B (IKK) SUPPRESSES NEUROINFLAMMATION AND PROTECTS AGAINST NEUROLOGICAL DEFICITS IN DEMYELINATING CNS DISEASE 731
CELL DEATH MECHANISMS CONTROLLED BY THE TNF FAMILY 732
PROGRAMMED, ACCIDENTAL AND SECONDARY NECROSIS CONVERGE ON SIMILAR CELLULAR DISINTEGRATION FEATURES 732
RIBOFLAVIN KINASE COUPLES TNF RECEPTOR 1 TO NADPH OXIDASE AND APOPTOSIS 733
ATIA, A MULTI-TASK PROTEIN THAT PROTECTS CELLS AGAINST TNF-INDUCED APOPTOSIS 733
A RNA INTERFERENCE SCREEN IDENTIFIES NOVEL REGULATORS OF TNF-INDUCED PROGRAMMED NECROSIS 734
COMPARTMENTALIZATION OF TNF-R1 SIGNALING: CASPASE-8 AND CASPASE-7 SEQUENTIALLY MEDIATE ACTIVATION OF ACID SPINGOMYELINASE IN INTERNALIZED TNF-R1 RECEPTOSOMES 735
TNF RECEPTOR-1 (P55) AND DISC COMPONENTS TRANSLOCATE TO THE MITOCHONDRIA AND NUCLEUS IN TNF-TREATED HEPATOCYTES 735
FAS LIGAND SECRETION AND SELF-TOLERANCE IS REGULATED BY THE WISKOTT-ALDRICH SYNDROME PROTEIN 736
TNFR1 HAS AN EARLY UBIQUITINATION-DEPENDENT, NF-B-INDEPENDENT CELL DEATH CHECKPOINT 737
TNFa AND Fasl CYTOTOXICITY IS REGULATED BY THE EXTRACELLULAR MATRIX PROTEIN CCN1 in vitro AND in vivo 738
NON-CANONICAL NF-B SIGNALING PATHWAY IS REQUIRED FOR TNFA AUTOCRINE AND NECROSIS IN L929 CELLS 739
THE FORM OF FAS LIGAND DETERMINES WHETHER RETINAL GANGLION CELLS SURVIVE OR DIE DURING GLAUCOMA 740
FATAL LYMPHOPROLIFERATIVE DISEASE IN FASL- AND TRAIL DOUBLE-DEFICIENT MICE DUE TO FAILURE OF MATURE LYMPHOCYTE ACTIVATION-INDUCED CELL DEATH 741
DcR2 PROTECTS CANCER CELLS FROM TRAIL-INDUCED APOPTOSIS BY ACTIVATING Akt 742
ANALYSIS OF KNOCKOUT/ KNOCKIN MICE THAT EXPRESS A MUTANT FasL LACKING THE INTRACELLULAR DOMAIN 742
XIAP LOSS CONVERTS FAS-INDUCED APOPTOSIS SIGNALING IN HEPATOCYTES FROM TYPE II INTO TYPE I 743
c- FLIP PROTEINS AT THE NEXUS POINT OF FATE-DETERMINING SIGNALS 743
Posters ROLES OF THE TNF FAMILY IN TISSUE HOMEOSTASIS AND NORMAL DEVELOPMENT 744
CHEMOKINES AS TARGETS OF EDA - A ROLE IN HAIR FOLLICLE DEVELOPMENT? 744
CASPASE-8 DEFICIENCY IN EPIDERMAL KERATINOCYTES TRIGGERS AN INFLAMMATORY SKIN DISEASE 745
ROLES OF THE TNF FAMILY IN CANCER 746
SUPPRESSION OF TUMOR GROWTH AND INTERRUPTION OF TUMOR ANGIOGENESIS BY SELECTIVE INHIBITION OF EITHER TNFR1/P55 OR TNFR2/75 IN MURINE MODEL OF LUNG CARCINOMA 746
INHIBITION OF TNFa/NIK/NF-kB TRANSDUCTION PATHWAY AS A POSSIBLE TARGET FOR PROSTATE CANCER TREATMENT 748
ERK and P38 PROMOTE SURVIVAL IN VITRO BY TNF-ALPHA STIMULATION IN PROSTATE CANCER 749
FUNCTION AND SIGNALING OF TRAIL IN PRIMARY HUMAN LEUKEMIA CELLS 750
STUDIES ON THE MECHANISM OF ACTION AND RESISTANCE TO TNFALPHA IN SOFT TISSUE SARCOMAS 750
LEUKOCYTE-DERIVED TNF- PROMOTES TUMOR GROWTH IN A SPONTANEOUS MODEL OF MAMMARY CARCINOGENESIS 751
ROLE OF B CELL IN TWO-STAGE SKIN CARCINOGENESIS 752
CO-EXPRESSION OF CD40L AND CD70 BY MELANOMA CELLS STIMULATES ANTI-TUMOUR IMMUNE RESPONSE 753
NOVEL ASPECTS OF SIGNALING ACTIVATION BY THE TNF FAMILY 754
ESSENTIAL ROLE OF TNF-INDUCIBLE ZINC FINGER PROTEIN A20 ON THE DEATH RECEPTOR-MEDIATED APOPTOTIC CELL DEATH THROUGH THE BLUNTING JNK SIGNALLING 754
ADP-RIBOSYLATION OF HUMAN TNF-ALPHA BY ADP-RIBOSYLTRANSFERASE-1 (ART1) 755
TRANSCRIPTIONAL NETWORKS AND SYSTEMS BIOLOGY 756
PKC- AKTS TOGETHER DURING TNF SIGNALLING 756
A PTP4A3 PEPTIDE PIMAP39 MODULATES TNF-alpha LEVELS AND ENDOTOXIC SHOCK 757
CROSS-TALK OF APOPTOSIS SIGNAL-REGULATING KINASE 1 (ASK1) AND HIF-1ALPHA PROTEIN AS ESSENTIAL PATHWAY FOR LIGAND-INDUCED TOLL-LIKE RECEPTOR 4-MEDIATED EXPRESSION OF PRO-INFLAMMATORY CYTOKINES 758
EXPRESSION OF TNFALPHA-ACTIVATED NFKAPPAB-DEPENDENT GENES IS AFFECTED BY HYPERTHERMIA AND ACTIVE HSF1 759
ROLES OF THE TNF FAMILY IN INFECTIOUS DISEASES AND INTERRELATIONSHIP OF THE TNF FAMILY AND PPR-SIGNALING 760
PHOSPHATASE PTP1B NEGATIVELY REGULATES MYD88- AND TRIF-DEPENDENT PROINFLAMMATORY CYTOKINE AND TYPE I INTERFERON PRODUCTION IN TLR-TRIGGERED MACROPHAGES 760
SHP-2 PHOSPHATASE DIFFERENTLY REGULATES MYD88- AND TRIF-DEPENDENT SIGNAL TRANSDUCTION IN LPS RESPONSE 761
CHARACTERISTICS AND FUNCTION OF ECTROMELIA GENE EVM008 761
IMPORTANCE OF TRAF1 SIGNALING DOWNSTREAM OF 4-1BB IN MEDIATING CD8 T CELL SURVIVAL 762
THE ROLE OF 4-1BBL IN RESCUING FUNCTIONALLY IMPAIRED HIV-SPECIFIC CD8 T CELLS 763
THE ROLE OF GITR IN CD8 T CELL RESPONSES TO INFLUENZA VIRUS 764
THE ROLE OF TRAF1 IN REGULATING TRAF2 STABILITY DOWNSTREAM OF 4-1BB SIGNALING 764
MOLECULAR CHARACTERIZATION OF CRMD, THE TNF AND CHEMOKINE DECOY RECEPTOR OF POXVIRUS 765
NOVEL ASPECTS OF IMMUNE REGULATION BY THE TNF FAMILY 766
STRUCTURAL AND FUNCTIONAL ANALYSIS OF DEATH RECEPTOR-6 766
CHARACTERIZATION OF DR6 SIGNALING. CELL SPECIFICITY IN APOPTOSIS INDUCTION AND NF- B ACTIVATION 767
ESSENTIAL ROLE OF TNFRSF25/TL1A IN THE DEVELOPMENT OF ALLERGIC LUNG INFLAMMATION AND INFLAMMATORY BOWEL DISEASE 768
APRIL (TNFSF13), A SIGNIFICANT IMMUNE MODULATOR IN A MODEL OF RHEUMATOID ARTHRITIS, IN ALLERGIC LUNG INFLAMMATION AND IN ORAL/MUCOSAL IMMUNITY 768
CONTROL OF LYMPHOCYTE FUNCTION AND REPERTOIRE BY THE TNF FAMILY 769
ROLES OF NIK IN THYMIC EPITHELIAL CELLS FOR THE ESTABLISHMENT OF CENTRAL TOLERANCE 769
LYMHOTOXIN-B-RECEPTOR SIGNALING IS REQUIRED TO LICENSE DC FOR CROSS-PRIMING 770
LYMPHOID TISSUE INDUCER CELLS CONTROL CD8A- DENDRITIC CELL HOMEOSTASIS VIA THE LYMPHOTOXIN-BETA RECEPTOR PATHWAY 771
ROLE OF TNFRI AS A COSTIMULATORY MOLECULE DURING THE EARLY PHASE OF TCR STIMULATION IN CD3 T LYMPHOCYTES 772
LYMPHOTOXIN RECEPTOR SIGNALING SUPPORTS A UNIQUE STROMAL CELL NICHE THAT SUPPORTS IGA CLASS SWITCH RECOMBINATION IN THE INTESTINAL LAMINA PROPRIA 773
FUNCTIONAL CHARACTERIZATION OF CHIMERICAL RECEPTORS RANK-TNFR2 AND ANALYSIS OF THEIR INTERACTION WITH ADAPTOR PROTEINS TRAF 774
TNF RECEPTOR ASSOCIATED FACTOR 1 (TRAF1) MODIFIES CRYSTALLINE SILICA INDUCED LUNG INJURY 774
TRAF1 REGULATES TWEAK AND LTAB2-INDUCED NFKB SIGNALLING 775
MECHANISMS OF PATHOLOGICAL THERAPEUTIC EFFECTS OF THE TNF FAMILY 776
TRAIL INDUCED CELL DEATH IN COLON CARCINOMA CELLS IN VIVO AND IN VITRO: SENSITISATION BY ONCOGENES AND BY OTHER THERAPEUTICS 776
RELATION OF PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINES WITH MEDIATORS OF BONE REMODELATING SYSTEM IN PSORIATIC ARTHRITIS 777
THE REGULATION OF THE AMOUNT OF EXTRA CELLULAR DNA FIBRES BY THE TNF SUPER FAMILY 778
INDUCTION OF PRIMARY SCLEROSING CHOLANGITIS-LIKE DISEASE BY DR5-MEDIATED APOPTOSIS 779
LUPUS SERUM INDUCES SKIN INFLAMMATION THROUGH TNFR1 SIGNALING PATHWAY 780
CD8 T CELL-MEDIATED IMMUNE RESPONSES AGAINST CROSS-PRESENTING LIVER SINUSOIDAL ENDOTHELIAL CELLS LEADS TO HEPATITIS 781
FUNCTIONAL CONSEQUENCES OF MUTATIONS IN TNFRSF1A, COMPARISON OF IN VITRO CELLULAR EVENTS TO FINDINGS FROM TISSUE SAMPLES ISOLATED FROM PATIENTS WITH TUMOUR NECROSIS FACTOR RECEPTOR-ASSOCIATED PERIODIC SYNDROME (TRAPS) 782
SIGNALING PATHWAYS OF MUTANT TUMOUR NECROSIS FACTOR RECEPTOR 1(TNFR1) 783
EFFECT OF INFLIXIMAB TREATMENT ON CIRCULATING MONOCYTES IN RHEUMATOID ARTHRITIS PATIENTS: DIFFERENCES BETWEEN EARLY AND LATE DISEASE 783
APRIL EXPRESSION AND TARGETTING IN AUTOIMMUNE DISEASES 784
TNF SHEDDING AND EPIDERMAL INFLAMMATION IS CONTROLLED BY JUN/AP-1 785
DISTINCT CONTRIBUTIONS OF T CELL-DERIVED AND MACROPHAGE-DERIVED TNF IN PATHOGENESIS OF COLLAGEN INDUCED ARTHRITIS AND EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS 786
HSP70 DEPENDENT ZINC PROTECTION AGAINST TNF-INDUCED LETHAL INFLAMMATION ALLOWS FOR A SAFER ANTITUMOR THERAPY 787
RESISTANCE OF SPRET/EI MICE TO TNF-INDUCED LETHAL SHOCK 787
ABLATION OF c-FLIP AUGMENTS CD95- AND GALACTOSAMINE/LPS-INDUCED LIVER INJURY THROUGH ACTIVATION OF c-JUN N-TERMINAL KINASE (JNK) 788
RATIONAL DESIGN OF NEW MEANS FOR THERAPEUTIC MODULATION OF FUNCTION OF THE TNF 789
MODULATORY EFFECT OF SILIBININ ON THE CYTOKINE PRODUCTION AND FUNGICIDAL ACTIVITY OF HUMAN MONOCYTES INFECTED IN VITRO WITH PARACOCCIDIOIDES BRASILIENSIS 789
APOPTOSIS-INDUCING ACTIVITY OF SOLUBLE TRAIL EXPRESSED IN MESENCHYMAL STEM CELLS ON HUMAN CANCER CELLS 790
ANALYSIS OF LIGAND RECEPTOR INTERACTION WITH NEW SINGLE CHAIN TNF DERIVATIVES 791
DOMINANT NEGATIVE TNF PROTECTS FROM MYCOBACTERIUM BOVIS BCG AND ENDOTOXIN-INDUCED LIVER INJURY WITHOUT COMPROMISING HOST IMMUNITY TO MYCOBACTERIUM TUBERCULOSIS AND BCG INFECTIONS 792
THE TUMOR NECROSIS FACTOR-A CONVERTING ENZYME (TACE) IS REGULATED BY PHYSIOLOGICAL IONIC STRENGTH 793
ENHANCED ANTI-TUMOR EFFICACY OF A DR5-SPECIFIC TRAIL VARIANT OVER RHTRAIL IN A BIOLUMINESCENT OVARIAN CANCER XENOGRAFT MODEL 793
TARGET CELL-RESTRICTED STIMULATION OF THE CD95 (APO-1/FAS) DEATH RECEPTOR WITH VARIOUS BISPECIFIC CD20XCD95 ANTIBODIES 794
SENSITIZATION OF PROSTATE CANCER CELLS TO TRAIL-MEDIATED APOPTOSIS BY THE TUMOR-SUPPRESSING MATAIRESINOL LIGNAN 795
RECEPTOR ACTIVATION BY SOLUBLE OX40 LIGAND AND 41BB LIGAND IS ENHANCED BY OLIGOMERIZATION AND CELL SURFACE IMMOBILIZATION 796
RELEVANCE OF OLIGOMERIZATION AND CELL SURFACE IMMOBILIZATION FOR THE ACTIVITY OF SOLUBLE VARIANTS OF CD27L AND GITRL 797
TRAIL FUSED TO SURFACTANT PROTEIN-D AND COLLECTIN-11 AS MODEL FOR TNF-SF COLLECTIN FUSION PROTEINS 797
MUTANT TNF ELICITS MUCOSAL AND SYSTEMIC IMMUNITY AGAINST HIV-1 AND INFLUENZA VIRUS 798
DEVELOPMENT OF A NOVEL METHOD USING PHAGE DISPLAY, GENE SHUFFLING AND IMPROVED RECEPTOR SELECTIVITY TO PRODUCE MUTANT TNFS 799
ANTI-INFLAMMATORY EFFECTS OF A NOVEL TNFR1-SELECTIVE ANTAGONISTIC TNF MUTANT ON ESTABLISHED MURINE COLLAGEN-INDUCED ARTHRITIS 800
RECEPTOR INTERACTION OF TUMOR NECROSIS FACTOR (TNF) BASED ON 3D STRUCTURAL ANALYSIS OF A FULLY ACTIVE TNFR1-SELECTIVE TNF MUTANT 801
THE DEVELOPMENT OF FULLY ACTIVE RECEPTOR-SELECTIVE TUMOR NECROSIS FACTOR (TNF) MUTANTS 802
THE ROLE OF HEPARAN SULFATE PROTEOGYCANS IN APRIL SIGNALLING 803
ENHANCEMENT OF ANTITUMOR PROPERTIES OF RHTRAIL BY AFFINITY INCREASE TOWARD ITS DEATH RECEPTORS 804
IMPROVED TUMOR CELL KILLING BY TRAIL REQUIRES SELECTIVE AND HIGH AFFINITY RECEPTOR ACTIVATION 805
COMPUTATIONAL DESIGN OF RECEPTOR SELECTIVE TRAIL VARIANTS 806
EFFICACY OF ANTI-TNF-A ANTIBODIES IN INTESTINAL CELL LINES SYSTEM 807
ROLES OF THE TNF FAMILY IN NEURONAL DEVELOPMENT, FUNCTION PATHOLOGY 808
TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND-RELATED SIGNAL TRANSDUCTION IN NEURODEGENERATIVE PROCESSES 808
APOPTOSIS REGULATION IN NEUROSECRETORY CELLS OF HYPOTHALAMUS OF AGED TNF-KNOCKOUT MICE 809
CELL DEATH MECHANISMS CONTROLLED BY THE TNF FAMILY 809
ASSOCIATION OF FASL AND CAVEOLIN-1 IN LIPID RAFTS IS ESSENTIAL FOR THE ONSET OF FASL-MEDIATED CELL DEATH 809
TNF ALPHA INDUCE SHEDDING OF CD30 AND CD45 AND LDH RELEASE FROM K-562 CELLS 810
DIFFERENTIAL ROLE OF FLIP ISOFORMS IN TNF-INDUCED CELL LIFE AND DEATH RESPONSES 811
DEATH WITHOUT LIGANDS: NOVEL APPROACH IN INDUCTION OF TNF RECEPTOR SUPERFAMILY MEDIATED CELL DEATH 811
INVOLVEMENT OF ENDOCYTOSIS IN TRAIL-R1/DR4 AND TRAIL-R2/DR5 TRAFFICKING AND SIGNALING 812
GENERATION OF LMP1-TR1/2 FUSION PROTEINS AND RECOMBINANT TRAIL 813
ENHANCED CASPASE-8 ACTIVATION WITHIN THE DISC PRIMES OVER THE MITOCHONDRIAL PATHWAY TO SENSITIZE DCR2 EXPRESSING CELLS TO TRAIL INDUCED CELL DEATH AFTER CHEMOTHERAPY 814
INHIBITION OF CASPASES ENHANCES THE CYTOTOXIC EFFECT OF TNF IN HUMAN MYELOMONOCYTIC U937 CELL LINE 814
ANCHORAGE DEPENDENCY OF TNF AND CD40 LIGAND-INDUCED MAPK SIGNALLING 815
LIFEGUARD DIRECTLY INTERACTS WITH NEUROBLASTOMA-DERIVED SULFHYDRYL OXIDASE 816
MEMBRANE FAS LIGAND CLEARS BACTERIA AND SOLUBLE FAS LIGAND PROTECTS HOST TISSUE DURING S. AUREUS INDUCED ENDOPHTHALMITIS 817
TRAIL RESISTANCE IN NON-TRANSFORMED CELLS IS PROVIDED BY MULTIPLE FACTORS 818
DOWNREGULATION OF C-FLIP PROMOTES CASPASE-DEPENDENT JNK ACTIVATION AND REACTIVE OXYGEN SPECIES ACCUMULATION IN TUMOR CELLS 819
SEVERAL MECHANISMS FOR THE REGULATION OF HUMAN T CELL BLAST ACTIVATION BY FASL AND APO2L/TRAIL 819
TNFALPHA-INDUCED ACTIVATION OF NFKAPPAB PROTECTS AGAINST UV-INDUCED APOPTOSIS SPECIFICALLY IN P53-PROFICIENT CELLS 820
INFLUENCE OF OPTINEURIN ON ADENOVIRUS E3-14.7K MEDIATED TNF-RESISTANCE 821
CD137-INDUCED CELL DEATH IN PERIPHERAL BLOOD MONONUCLEAR CELLS 822
REGULATION OF CELL DEATH BY c-FLIP PHOSPHORYLATION 822
MATHEMATICAL MODELING OF APOPTOSIS AS A FUNCTION OF C-FLIP TURNOVER AND AT RANDOM PARAMETER DISTRIBUTIONS 823
RIP1, A JACK-OF-ALL-TRADES 824
Subject Index 825

Produkt-Details

• Erscheint lt. Verlag: 9.12.2010
• Reihe/Serie: Advances in Experimental Medicine and Biology
• Reihe/Serie: Advances in Experimental Medicine and Biology
• Zusatzinfo: XXXVI, 844 p.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Studium ► Querschnittsbereiche ► Infektiologie / Immunologie
• Themenwelt: Naturwissenschaften ► Biologie ► Mikrobiologie / Immunologie
• Themenwelt: Technik
• ISBN-10: 1-4419-6612-9 / 1441966129
• ISBN-13: 978-1-4419-6612-4 / 9781441966124