TNF-a

1
TNF-a
2
BMP MIF
TNF-a IL-1 IL-6 IL-7 IL-8 IL18 MIF angiopoietin-1
SDGF, FGF
IgG
IL-1 TNF-a GM-CSF IL-6 MIF IL-12 IL-18
IFN-g IL-2 IL-4 IL-6 IL-5 IL-17 MIF
effector T-cells
T
K Tc NK-IFN-g
3
2 types of TNF receptor
Location of TNFR in steady state
express constitutively
Dead signal ? apoptosis
TNFR-I (p55, CD120a)
Down regulation mechanism
TNF-a overproduction
TNFR cleaved into soluble TNFRs
Inducible
? cytokines production
LPS
TNFR-II (p75, CD120b)
TNF-a-TNFR complex
4
Signal Transduction

• Transcription associated protein

• Protein kinase cascade

TNFR I
caspase

• Transcription factors

TNF-a, IL-1b, IL-6, IL-8, COX2, INOS
NF-kB
NIK
TNFR II
Protein transcription
AP-1
MAPK
IL-1, IL-6, IL-8, IL-10, GM-CSF Adhesion
molecules PGE2, collagenase
Rx target
Kinase cascade (MAPK, NIK, caspase)
Transcription factors (AP-1, NF-kB)
5
TNF family proteins
Therapeutic implication
Lymphocyte
Belimumab Lymphostat RA, SLE
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
7
Y
Y
Protein receptor antagonist
Monoclonal Ab
Soluble receptor
TNF-a Blockade