TNF-a

IL-1 TNF-a ** IFN-g B IL-2 MMP T T1,2 IgG IL-6 IL-4 MIF IL-6 IL-12 BMP MIF TNF-a IL-1 IL-6 IL-7 IL-8 IL18 MIF angiopoietin-1 SDGF, FGF IL-1 TNF-a ** GM-CSF IL-6 MIF IL-12 IL-18 IgG IFN-g IL-2 IL-4 IL-6 IL-5 IL-17 MIF B MIF effector T-cells MMP IL-18 T T1,2 K Tc NK-IFN-g IFN-g IL-2

Location of TNFR in steady state 2 types of TNF receptor Location of TNFR in steady state express constitutively Dead signal → apoptosis TNFR-I (p55, CD120a) TNF-a overproduction Down regulation mechanism  soluble TNFRs production TNFR cleaved into soluble TNFRs Inducible → cytokines production LPS TNFR-II (p75, CD120b) endocytosis TNF-a-TNFR complex

Rx target Signal Transduction Transcription associated protein FADD: factor asso death domain TRADD- TNFR I asso death domain Signal Transduction Transcription associated protein TNFR I Protein kinase cascade caspase Transcription factors TNF-a, IL-1b, IL-6, IL-8, COX2, INOS NF-kB NIK TNFR II AP-1 Protein transcription MAPK IL-1, IL-6, IL-8, IL-10, GM-CSF Adhesion molecules PGE2, collagenase Rx target RIP: R. interacting protein TNFR associated factors (TRAF 1-6) Kinase cascade (MAPK, NIK, caspase) Transcription factors (AP-1, NF-kB)

TNF family proteins Ig Therapeutic implication Lymphocyte anti fas mAb TRAIL dead R 4 Therapeutic implication TRAIL dead R 5 Lymphocyte Ig BLyS BAFF-R Belimumab Lymphostat RA, SLE TACI APRIL BCMA Humanized mAb TRAIL = TNF related apoptosis-inducing ligand BAFF-R = B-cell activating factor receptor TACI = transmembrane activator and calcium modulator and cyclophilin ligand-interactor BCMA = B-cell maturation BLyS = B-lymphocyte stimulator (increase serum level in SLE) differentiation, activation, survival APRIL = a proliferation inducing ligand

Rx Target RANK (receptor activator NF-kB) = TNFR family member RANKL / ODF = RANK ligand / osteoclast diff.factor TRAF (TNF-R activating factors) Rx Target

Y Y TNF-a Blockade TNF-a TNFR TNFR TNFR Protein receptor antagonist Monoclonal Ab Soluble receptor TNF-a Blockade