1. TNF-a

2. 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

3. 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

4. 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)

5. 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

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

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