2. 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
Odisha NET Academy-09337727724
5. 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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6. 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
comple
x
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7. 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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8. Apoptosome:
“wheel of death”
The Mitochondrial Apoptotic pathway
Bax,Bak
Bcl-2,Bcl XL
Caspase-8 signal or
Pro apoptotic signal dominants
on Anti apoptotic signal
Inh ibits
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9. TNF-alpha caN sigNal
To NF-kB TraNscripTioN FacTors
*NF-kB factors are mostly anti-apoptotic
Activate pro-survival
Bcl-XL,Bcl-2
IAPs
Activate pro-apoptotic
FAS, FAS Ligand
P53
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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10. 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
11. 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
12. What is the molecular basis of
the Paradox? Cellular Context
NFκB:
Life
Caspases:
death
IL-1
TNFα
Conclusion:
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