Contents

Preface by David Wallach . . . . . . . . . . . . . . . . . . . . . . . . . . v

Preface by Marc Feldmann . . . . . . . . . . . . . . . . . . . . . . . . . ix

Part I Roles of the TNF Family in Tissue Homeostasisand Normal Development

1 Workshop Summary: Roles of the TNF Family in NormalDevelopment and Cancer . . . . . . . . . . . . . . . . . . . . . . . 3Nancy H. Ruddle

2 TNF Conference 2009: Beyond Bones – RANKL/RANKin the Immune System . . . . . . . . . . . . . . . . . . . . . . . . 5Andreas Leibbrandt and Josef M. Penninger

3 The Edar Subfamily in Hair and Exocrine GlandDevelopment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Marja L. Mikkola

4 High Endothelial Venule Reporter Mice to ProbeRegulation of Lymph Node Vasculature . . . . . . . . . . . . . . . 35Kevin L. Bentley, Sharon Stranford, Shan Liao,Rawad M. Mounzer, Frank H. Ruddle, and Nancy H. Ruddle

5 Eiger and Wengen: The Drosophila Orthologsof TNF/TNFR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Tatsushi Igaki, Hiroshi Kanda, Hideyuki Okano, Tian Xu,and Masayuki Miura

Part II Novel Aspects of Signaling Activation by the TNFFamily: Novel Aspects of the Functions of the TRAFsand cIAPs

6 Workshop Summary: Novel Aspects of the Functions of theTRAFs and cIAPs . . . . . . . . . . . . . . . . . . . . . . . . . . . 53John Silke and Domagoj Vucic

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7 TRAF2 and Cellular IAPs: A Critical Link in TNFRFamily Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63Domagoj Vucic

8 New Perspectives in TNF-R1-Induced NF-κB Signaling . . . . . . 79Ian E. Gentle and John Silke

9 Structural Studies of NEMO and TRAF6: Implicationsin NF-κB Activation . . . . . . . . . . . . . . . . . . . . . . . . . . 89Hao Wu, Yu-Chih Lo, and Qian Yin

Part III Novel Aspects of Signaling Activation by the TNF:Ubiquitin Modification of Signaling Proteins

10 Modification by Single Ubiquitin MoietiesRather Than Polyubiquitination Is Sufficientfor Proteasomal Processing of the p105 NF-κB Precursor . . . . . 95Yelena Kravtsova-Ivantsiv, Shai Cohen,and Aaron Ciechanover

11 Selective Binding of Linear Ubiquitin Chainsto NEMO in NF-kappaB Activation . . . . . . . . . . . . . . . . . 107Fumiyo Ikeda, Simin Rahighi, Soichi Wakatsuki,and Ivan Dikic

12 The Linear Ubiquitin Chain Assembly Complex(LUBAC) Forms Part of the TNF-R1 Signalling Complexand Is Required for Effective TNF-Induced GeneInduction and Prevents TNF-Induced Apoptosis . . . . . . . . . . 115Christoph H. Emmerich, Anna C. Schmukle, Tobias L. Haas,Björn Gerlach, Stefanie M. Cordier, Eva Rieser,and Henning Walczak

13 Temporal Control of TNFα Signaling by Miz1 . . . . . . . . . . . 127Anning Lin

Part IV Novel aspects of Signaling Activation by the TNFFamily: TNF Signaling and Gene Regulatory Networks

14 Large-Scale RNAi Screens to Dissect TNF and NF-κBSignaling Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . 131Marie Metzig, Dorothee Nickles, and Michael Boutros

15 Pathogenic Role of IL-6 Combined with TNF-α or IL-1in the Induction of Acute Phase Proteins SAA and CRPin Chronic Inflammatory Diseases . . . . . . . . . . . . . . . . . . 141Kazuyuki Yoshizaki

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16 Understanding Life and Death at CD95 . . . . . . . . . . . . . . . 151Carina Pforr, Leo Neumann, Roland Eils, Peter H. Krammer,and Inna N. Lavrik

17 Unique Personalities Within the NF-κB Family: DistinctFunctions for p65 and RelB in the Osteoclast . . . . . . . . . . . . 163Deborah Veis Novack

Part V Roles of the TNF Family in Infectious Diseasesand Interrelationship of the TNF Family and PatternRecognition Receptor Signaling: Roles of the TNFFamily in Infectious Diseases

18 Workshop Summary: Functions of the TNF Family inInfectious Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 171Michael Wortzman and Tania H. Watts

19 Role of 4-1BBL and TRAF1 in the CD8 T Cell Responseto Influenza Virus and HIV . . . . . . . . . . . . . . . . . . . . . . 177Tania H. Watts, Gloria H.Y. Lin, Chao Wang,Ann J. McPherson, Laura M. Snell, and Laurent Sabbagh

20 Roles of Soluble and Membrane TNFand Related Ligands in Mycobacterial Infections:Effects of Selective and Non-selective TNF InhibitorsDuring Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187Irene Garcia, Maria L. Olleros, Valerie F.J. Quesniaux,Muazzam Jacobs, Nasiema Allie, Sergei A. Nedospasov,David E. Szymkowski, and Bernhard Ryffel

21 Poxviral TNFRs: Properties and Role in Viral Pathogenesis . . . 203Alí Alejo, Sergio M. Pontejo, and Antonio Alcami

22 Heme Sensitization to TNF-Mediated Programmed Cell Death . . 211Raffaella Gozzelino and Miguel P. Soares

23 TNF-α and TNFR in Chagas Disease: From ProtectiveImmunity to Pathogenesis of Chronic Cardiomyopathy . . . . . . 221Joseli Lannes-Vieira, Isabela Resende Pereira,Nathália Ferreira Vinagre, and Lucia Elena Alvarado Arnez

24 Lymphotoxin’s Link to Carcinogenesis:Friend or Foe? From Lymphoid Neogenesisto Hepatocellular Carcinoma and Prostate Cancer . . . . . . . . . 231Monika Julia Wolf, Gitta Maria Seleznik,and Mathias Heikenwalder

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Part VI Roles of the TNF Family in Infectious Diseasesand Interrelationship of the TNF Family and PatternRecognition Receptor Signaling: Interrelationshipof the TNF Family and Pattern Recognition Receptor Signaling

25 Anti-inflammatory Functions of Caspase-8 . . . . . . . . . . . . . 253Akhil Rajput, Tae-Bong Kang, Konstantin Bogdanov,Jin-Chul Kim, Tehila Ben-Moshe, Andrew Kovalenko,and David Wallach

26 Endogenous Ligand-Induced Activation of TLR4 in Pre-metastatic Phase Is Both Downstream and Upstream ofTNF Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261Yoshiro Maru

Part VII Novel Aspects of Immune Regulation by the TNF Family

27 Introductory Words About TL1A/DR3 . . . . . . . . . . . . . . . 271Stephan R. Targan

28 Introductory Words About TWEAK/Fn14 . . . . . . . . . . . . . 275Linda C. Burkly

29 Insights into TL1A and IBD Pathogenesis . . . . . . . . . . . . . . 279David Q. Shih, Kathrin S. Michelsen, Robert J. Barrett,Eva Biener-Ramanujan, Rivkah Gonsky, Xiaolan Zhang,and Stephan R. Targan

30 The Role of TNFRSF25:TNFSF15 in Disease. . . and Health? . . . 289Taylor H. Schreiber, Dietlinde Wolf, and Eckhard R. Podack

31 Identification of New Candidates as Mucosal VaccineAdjuvant in TNF Family Cytokines . . . . . . . . . . . . . . . . . 299Hiroyuki Kayamuro, Yasuo Yoshioka, Yasuhiro Abe,Kazufumi Katayama, Shuhei Arita, Tetsuya Nomura,Tomoaki Yoshikawa, Norio Itoh, Haruhiko Kamada,Shin-ichi Tsunoda, and Yasuo Tsutsumi

32 The TWEAK/Fn14 Pathway in Tissue Remodeling:For Better or for Worse . . . . . . . . . . . . . . . . . . . . . . . . 305Linda C. Burkly and Taeko Dohi

33 TWEAK and the Kidney: the Dual Roleof a Multifunctional Cytokine . . . . . . . . . . . . . . . . . . . . 323Ana Ortiz, M.D. Sanchez-Niño, M.C. Izquierdo,L.M. Blanco-Colio, R. Selgas, M. Ruiz-Ortega, J. Egido,and Ana B. Sanz

34 TWEAK and TNF Regulation of Sclerostin: A NovelPathway for the Regulation of Bone Remodelling . . . . . . . . . 337David M. Findlay and Gerald J. Atkins

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Part VIII Control of Lymphocyte Function and Repertoireby the TNF Family

35 Workshop Summary: Control of Lymphocyte Functionand Repertoire by the TNF Superfamily . . . . . . . . . . . . . . 351Carl F. Ware and Jeffrey L. Browning

36 The Canonical and Unconventional Ligandsof the Herpesvirus Entry Mediator . . . . . . . . . . . . . . . . . 353Timothy C. Cheung and Carl F. Ware

37 The Lymphotoxin Pathway as a Novel Regulatorof Dendritic Cell Function . . . . . . . . . . . . . . . . . . . . . . 363Leslie Summers deLuca and Jennifer L. Gommerman

38 Involvement of the Cytokine Receptor CD137 in MurineHematopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375Dongsheng Jiang, Qianqiao Tang, and Herbert Schwarz

39 LTBR-Pathway in Sjogren’s Syndrome: CXCL13 Levelsand B-cell-Enriched Ectopic Lymphoid Aggregatesin NOD Mouse Lacrimal Glands Are Dependenton LTBR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383Roy A. Fava, Jeffrey L. Browning, Margaret Gatumu,Kathrine Skarstein, and Anne-Isine Bolstad

40 MEK Kinase 1: Kinase Domain Deficiency in MiceReveals a Role in Orchestrating the Thymus-DependentImmunity and TNFR Family Signaling . . . . . . . . . . . . . . . 391Ewen Gallagher

Part IX Advances in Applying Our Knowledge to Therapy:Mechanisms of Pathological and Therapeutic Effectsof the TNF Family

41 Introduction to the Session “Mechanisms of Pathologicaland Therapeutic Effects of the TNF Family” . . . . . . . . . . . . 401Claude Libert

42 Mechanisms Regulating TNF-Driven Gut and JointInflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403Dirk Elewaut, Peggy Jacques, Lode Melis, and Koen Venken

43 Lessons from Anti-TNF Biologics: Infliximab Failurein a TRAPS Family with the T50M Mutationin TNFRSF1A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409Belinda Nedjai, Niamh Quillinan, Robert J. Coughlan,Leigh Church, Michael F. McDermott, Graham A. Hitman,and Mark D. Turner

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44 Modalities of Experimental TNF Blockade In Vivo:Mouse Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421A.A. Kruglov, A.V. Tumanov, S.I. Grivennikov,Yu.V. Shebzukhov, A.A. Kuchmiy, G.A. Efimov,M.S. Drutskaya, J. Scheller, D.V. Kuprash,and Sergei A. Nedospasov

45 Tumor Necrosis Factor-α Signaling via TNFR1/p55Is Deleterious Whereas TNFR2/p75 SignalingIs Protective in Adult Infarct Myocardium . . . . . . . . . . . . . 433Raj Kishore, Tengiz Tkebuchava, Sharath P. Sasi,Marcy Silver, Hu-Ya Gilbert, Young-Sup Yoon, Hee-YoungPark, Tina Thorne, Douglas W. Losordo,and David A. Goukassian

46 TNF-α Regulation of CD38 Expression in Human AirwaySmooth Muscle: Role of MAP Kinases and NF-κB . . . . . . . . . 449Joseph A. Jude, Reynold A. Panettieri, Timothy F. Walseth,and Mathur S. Kannan

47 Functional Consequences of Disease-Associated Mutationsin TNFR1 Elucidated by Transcriptome Analysis . . . . . . . . . 461Susana L. Rebelo, Paul M. Radford, Susan E. Bainbridge,Ian Todd, and Patrick J. Tighe

48 Tumor Necrosis Factor-α and Kidney Function:Experimental Findings in Mice . . . . . . . . . . . . . . . . . . . 471Dewan S.A. Majid

49 Strategies to Inhibit the Toxicity of Systemic TNF Treatment . . . 481Filip Van Hauwermeiren, Leen Puimège, Sofie Vandevyver,Tom Van Bogaert, Ineke Vanlaere, Liesbeth Huys,Lien Dejager, and Claude Libert

Part X Advances in Applying our Knowledge to Therapy:Rational Design of New Means for TherapeuticModulation of Function of the TNF Family

50 Workshop Summary: Introduction to Rational Designof New Means for Therapeutic Modulation of Functionof the TNF Family . . . . . . . . . . . . . . . . . . . . . . . . . . . 487Klaus Pfizenmaier and David E. Szymkowski

51 Anti-inflammatory Effects of a Novel TNFR1-SelectiveAntagonistic TNF Mutant on Established MurineCollagen-Induced Arthritis . . . . . . . . . . . . . . . . . . . . . . 493Yasuhiro Abe, Tetsuya Nomura, Yasuo Yoshioka,Haruhiko Kamada, Shin-ichi Tsunoda, and Yasuo Tsutsumi

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52 A Proliferation-Inducing Ligand (APRIL):The Development of Antagonistic Agentsas Potential Therapeutics and Deciphering the Roleof Heparan Sulphate Proteoglycans (HSPGs) in APRILSignalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501Fiona Kimberley, Marco Guadagnoli, Hans van Eenennaam,and Jan Paul Medema

53 Genetic Engineering of Death Ligands for Improvementof Therapeutic Activity . . . . . . . . . . . . . . . . . . . . . . . . 507Jeannette Gerspach, Britta Schneider, Nicole Müller,Tina Otz, Harald Wajant, and Klaus Pfizenmaier

54 Computational Design of TNF Ligand-BasedProtein Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . 521Almer M. van der Sloot and Wim J. Quax

Part XI Roles of the TNF Family in Neuronal Development,Function, and Pathology

55 Workshop Summary: Roles of the TNF Family inNeuronal Development, Function and Pathology . . . . . . . . . . 537Malú G. Tansey and Tony Wyss-Coray

56 TNF: A Key Neuroinflammatory Mediatorof Neurotoxicity and Neurodegeneration in Modelsof Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . 539Melissa K. McCoy, Kelly A. Ruhn, Armin Blesch,and Malú G. Tansey

57 The Contribution of TNFα to Synaptic Plasticityand Nervous System Function . . . . . . . . . . . . . . . . . . . . 541David Stellwagen

58 Intracellular and Intercellular Cross Talk Between NGFand TNF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559Yoshinori Takei and Ronald Laskey

59 TNFR2 – Target for Therapeutics AgainstNeurodegenerative Diseases? . . . . . . . . . . . . . . . . . . . . . 567Ingrid M. Nijholt, Ivica Granic, Paul G.M. Luiten,and Ulrich L.M. Eisel

60 A Role for Neuronal NF-κB in SuppressingNeuroinflammation and Promoting Neuroprotectionin the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575Mary Emmanouil, Era Taoufik, Vivian Tseveleki,Sotiris-Spyros Vamvakas, and Lesley Probert

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Part XII Cell Death Mechanisms Controlled by the TNF Family

61 Workshop Summary: Cell Death Mechanisms Controlledby the TNF Family . . . . . . . . . . . . . . . . . . . . . . . . . . 585John E. Eriksson and Peter Vandenabeele

62 A RNA Interference Screen Identifies RIP3 as an EssentialInducer of TNF-Induced Programmed Necrosis . . . . . . . . . . 589YoungSik Cho, Sreerupa Challa, and Francis Ka-Ming Chan

63 The Extracellular Matrix Protein CCN1 Dictates TNFαand FasL Cytotoxicity In Vivo . . . . . . . . . . . . . . . . . . . . 595Chih-Chiun Chen, Vladislava Juric, and Lester F. Lau

64 Compartmentalization of TNF-Receptor 1 Signaling:TNF-R1-Associated Caspase-8 Mediates Activationof Acid Sphingomyelinase in Late Endosomes . . . . . . . . . . . 605Uwe Bertsch, Bärbel Edelmann, Vladimir Tchikov,Supandi Winoto-Morbach, and Stefan Schütze

65 TNF/TNF Receptor 1-Mediated Apoptosis in Hepatocytes . . . . 617Hyun-Ae Eum and Timothy R. Billiar

66 Regulation of Cell Death by c-FLIP Phosphorylation . . . . . . . 625Tomoko Asaoka, Aura Kaunisto, and John E. Eriksson

Appendix I:Contributors to Abstracts of Talks and Posters at the 12th

TNF Conference . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631

Appendix II:Abstracts of Talks and Posters Presented at the 12th TNFConference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829

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