Tnf alpha presentation


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Tnf alpha presentation

  1. 1. Tumor Necrosis Factor Implication Of Apoptosis and Cell Growth Arun kumar Pradhan ONA Odisha NET Academy-09337727724
  2. 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
  3. 3. D D I S C Odisha NET Academy-09337727724
  4. 4. DEATH signals TNF- alpha / CD95 ligand / Fas ligand Death receptors, e.g. CD95 Death domains Odisha NET Academy-09337727724
  5. 5. Binding to the receptor induces receptors to cluster and trimerize After binding to ligand, receptors form trimers Death domains TNF/Fas ligand trimer Odisha NET Academy-09337727724
  6. 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 Odisha NET Academy-09337727724
  7. 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 Odisha NET Academy-09337727724
  8. 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 Odisha NET Academy-09337727724
  9. 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 Odisha NET Academy-09337727724
  10. 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. 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. 12. What is the molecular basis of the Paradox? Cellular Context NFκB: Life Caspases: death IL-1 TNFα Conclusion: Odisha NET Academy-09337727724
  13. 13. ?Odisha NET Academy-09337727724
  14. 14. Thank ouOdisha NET Academy-09337727724