The NF-κB pathways in connective tissue diseases

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1 κ The NF-κB pathways in connective tissue diseases TETSUO KUBOTA (Associate Professor) Tokyo Medical and Dental University Graduate School of Health Care Sciences NF-κB nuclear factor-kappa B NF-κB in vivo NF-κB NF-κB systemic lupus erythematosus SLE antiphospholipid syndrome APS NF-κB κ NF-κB N DNA 2 Rel-homology domain RHD 5 RelA p65 RelB c-rel NF-κB1 p50/p105 NF-κB2 p52/p RHD nuclear localization signal NLS IκBα IκBβ IκBε IκB inhibitor of κb NF-κB κ p50 p52 p105 p100 C IκB ankyrin-repeat motifs ANK NF-κB κ NF-κB canonical classical pathway non-canonical alternative pathway Canonical 8

2 κ pathway TNF TNF-R IL-1 IL-1R Toll-like TLR T TCR RelA p65 :p IKKα IKKβ NEMO NF-κ B essential modifier IKKγ IκB kinase 3 IKK trimer IκBα IκBα RelA NLS RelA:p κ β β κ κ κ non-canonical pathway CD40 lymphotoxin-β LTβR RANK recepter activator of NF-κ B BAFF BAFF-R 3 NF-κB-inducing kinase NIK IKKα 2 p100 C ankyrin repeat N p52 RelB 2 B T NF-κB NF-κB 2 NF-κB 2 promiscuous expression T 9

3 NF-κB IL-1 Toll-like TRAF6 TRAF6 T 3 NF-κB2 p100 NF-κB2 4 T negative selection IκB NS NFκB 5 B B BCR recombinase-activating gene RAG BCR RAG RelA crel NF- B1 p50 6 κ BAFF B cell-activating factor; BLyS TNF T B SLE BAFF BAFF BAFF-R TACI transmembrane activator and CAML interactor BCMA B cell maturation antigen 3 BCMA TACI TNF APRIL a proliferation-inducing ligand BAFF-R BAFF 4 3 NF-κB canonical pathway non-canonical pathway BAFF-R SLE :9 50,000 CNS CNS DNA RNP Sm CD20 B κ κ BAFF B DNA SLE Enzler 7 B NF-κB BAFF NF-κB 10

4 κ BAFF noncanonical pathway marginal zone B canonical pathway DNA IgG 4 BAFF fullblown SLE NF-κB SLE BAFF BAFF Doreau 8 IL-17 BAFF BCR B IL-17 BAFF B IL-17 BAFF NF-κB Twist-1 IL-17 SLE CD3 + CD4 - CD8 - T IL-17 IL-17 NF-κB c-jun NH2-terminal kinase JNK MAP kinase 9 Wu 10 B PI3K/ AKT/mTOR MEK1/Erk1/2 p38 NF-κB Bcl-2 mtor kinase RAD001 DNA RAD001 B AKT Erk1/2 NF-κB Bcl-2 CDK2 STAT3 B k APS 1 APS 2 APS 2 APS SLE 50% β2-glycoprotein I 11 López- Pedrera 12 APS tissue factor TF p38 MAP kinase NF-κB MEK-1/ERK APS IgG TF APS CCR1 CCR3 CCR4 CXCR4 CX3CL1 P-selectin β2-glycoprotein I IL-1β TNFα CX3CL1 CCL5 CX3CL1 CCL5 5 IL-1β TNFα CX3CL1 CCL5 NK-κB NF-κB DHMEQ 13 NF-κB APS 14 in vivo NF-κB MG

5 β NF-κB NF-κB NF-κB 16 NF-κB TNFα NF-κB 1 Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function. Nat Rev Mol Cell Biol ; 8: (2007) 2 Tak PP, Firestein GS. NF-κB: a key role in inflammatory diseases. J Clin Invest ;107 :7-11. (2001) 3 Akiyama T, Maeda S, Yamane S, et al. Dependence of selftolerance on TRAF6-directed development of thymic stroma. Science ; 308: (2005) 4 Zhang B, Wang Z, Ding J, et al. NF-κB2 is required for the control of autoimmunity by regulating the development of medullary thymic epithelial cells. J Biol Chem ; 281: (2006) 5 Fiorini E, Schmitz I, Marissen WE, et al. Peptide-induced negative selection of thymocytes activates transcription of an NF-κB inhibitor. Mol Cell ; 9: (2002) 6 Verkoczy L, Aït-Azzouzene D, Skog P, et al. A role for nuclear factor kappa B/Rel transcription factors in the regulation of the recombinase activator genes. Immunity ; 22: (2005) 7 Enzler T, Bonizzi G, Silverman GJ, et al. Alternative and classical NF-κB signaling retain autoreactive B cells in the splenic marginal zone and result in lupus-like disease. Immunity ; 25: (2006) 8 Doreau A, Belot A, Bastid J, et al. Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus. Nat Immunol ; 10: (2009) 9 Schwandner R, Yamaguchi K, Cao Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF) 6 in interleukin 17 signal transduction. J Exp Med ;191: (2000) 10 Wu T, Qin X, Kurepa Z, et al. Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus. J Clin Invest ; 117: (2007) 11 Meroni PL, Ronda N, De Angelis V, et al. Role of anti-b 2 glycoprotein I antibodies in antiphospholipid syndrome. In vitro and in vivo studies. Clin Rev Allergy Immunol ; 32: (2007) 12 López-Pedrera C, Buendía P, Cuadrado MJ, et al. Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF- B/Rel proteins via the p38 mitogen-activated protein kinase pathway, and of the MEK-1/ERK pathway. Arthritis Rheum ; 54: (2006) 13 Yamamoto M, Horie R, Takeiri M, et al. Inactivation of NF-κB components by covalant binding of (-)-dehydroxymethylepoxyquinomicin to specific cysteine residues. J Med Chem ; 51: (2008) 14 Kubota T, Fukuya Y, Hashimoto R, et al. Possible involvement of chemokine-induced platelet activation in thrombophilic diathesis of antiphospholipid syndrome. An attractive target for the NF-κB-specific inhibitor DHMEQ. Ann N Y Acac Sci ; 1173: (2009) 15 Montiel-Manzano G, Romay-Penabad Z, De Martínez EP, et al. In vivo effects of an inhibitor of nuclear factor-kappa B on thrombogenic properties of antiphospholipid antibodies. Ann N Y Aca d Sci ; 1108: (2007) 16 Pasparakis M. Regulation of tissue homeostasis by NF-κB signalling: implications for inflammatory diseases. Nat Rev Immunol ; 9: (2009) 12

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