TNFα activation of NFκB signaling

TNFTNF--αα

Activated Macrophage

Tumor Necrosis Factor: TNFα

Inflammation Proliferation Apoptosis Immune Response

Somatic cells&

Endothelium

Structure of TNFα

212 amino acidmembrane protein

TACE

185 amino acidsoluble protein

TNFα Activation of TNF Receptors

TNFα Activates Multiple Signaling PathwaysSO

DD

SOD

D

SOD

D

TNF

TNFα Diseases and Treatments

1. Alzheimer2. Parkinson’s3. Stroke-Neuoroinflammation-mediated cell death

Suspected of playing a role:

Anti-TNFα therapy for Crohn’s disease, rheumatoid arthritis, asthma

Anti-TNF antibody Soluble TNFRII-human Fc fusion

2. Infliximab1. Adalimumab Etanercept

Local vs Systemic Infection (Sepsis)TNFα activation

Local Liver&

spleen

EdemaLocal activity

DeathCleared infection

Phagocytosis Organ failure

NF-kB Signaling Pathways

NF- κB Family of Transcription Factors

5’-NNNNNNNNNGGRNWYYCCNNNNNNNNNNNN-3’

Bind as dimers to κB DNA sites

W:A or TY: C or T

p65

p50

Structure p50-p65 (RelA) NF-kB complex

NF-kB Regulators

Classical/Canonical NF-kB Signaling PathwayTNFα

An Alternative NF-kB Signaling PathwayLTβ

Numerous Signal Pathways can Activate NF-kB