Tumor Necrosis Factor Implication Of Apoptosis and Cel l Growth

Arun kumar PradhanONA

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TNF α •Also called cachectin•Produced by macrophages and Mast cells •TNF alpha is a inflammatory cytokine

•Target tissue: tumour cells and Inflammatory cells

•Responsible for extensive weight loss (cachexia) associated with chronic inflammation.

TNF β•Also called lymphotoxin•produced by TH1 and Tc cells

•Target tissue: tumour cells and macrophage and neutrophils

•Has cytotoxic activity

• Enhances the phagocytic activity.

Apoptosis:-• Apoptosis from Greek, meaning “falling off” (also called programmed cell death)

• Complex program of self-destruction,triggered by a variety of stimuli and involving the activation of caspase enzymes, that results in quick fragmentation and phagocytosis of a cell

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D

DISC

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DEATH signals

TNF-alpha / CD95 ligand / Fas ligand

Death receptors, e.g. CD95

Death domains

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Binding to the receptor induces receptors to cluster and trimerize

After binding to ligand, receptors form trimers

Death domains

TNF/Fas ligand trimer

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FADD (Fas associated death domain protein)

is recruited via its death domain

DED (death effector domain) of FADD recruits pro-caspase 8 via its DED

FADD-CASP8 complex brings multiple pro-caspase 8 molecules in close proximity

(‘induced proximity’ aggregation results in their cross-activation). Activated caspase-8

(a heterotetramer) is released from DISC into the cytoplasm

DISC complex

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caspase-8 cleaves pro-apoptotic BID

protein.

BID interacts with the pro-apoptotic

BCL2 relatives BAX and BAK

This amplifies apoptosis induction

through the cell-extrinsic

pathway

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Apoptosome:“wheel of death”

The Mitochondrial Apoptotic pathway

Bax,BakBcl-2,Bcl XL

Caspase-8 signal orPro apoptotic signal dominants

on Anti apoptotic signal

Inh ibits

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TNF-alpha caN sigNal To NF-kB TraNscripTioN FacTors

*NF-kB factors are mostly anti-apoptotic

Activate pro-survival Bcl-XL,Bcl-2IAPs

Activate pro-apoptoticFAS, FAS LigandP53

inflammatory cytokines, chemokines,

immunoreceptors, and cell adhesion molecules

Tissue specific decision

One of the `central mediators

of the immune response

NF-kB

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TNF-alpha can signal to NF-kappaB transcription factors.

Binding of TNF-alpha to TNFR

TRADD recruited

IKK kinase recruited

IKK phosphorylate IkB

IkB degraded

P50/p65(NF-kappaB)Free to act as TF Odisha NET Academy-09337727724

TNF-alpha can signal to NF-kappaB transcription factors.

In the cytoplasm, NF-kB is inhibited by IkB (inhibiitor of NF-kappa B)

Upstream activating signal (e.g., binding of TNF to its receptor) may cause phosphorylation of IkB

by IKK (IkB kinase).

Cell survival & GrowthOdisha NET Academy-09337727724

What is the molecular basis of the Paradox? Cellular Context

NFκB:

Life

Caspases:

death

IL-1 TNFα

Conclusion:

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?Odisha NET Academy-09337727724

Thank

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