Figure 2.

Different TNFR complex formed downstream of TNF. TNF (tumor necrosis factor) can induce the formation of different complexes with diverse outcomes depending on the conditions. In a homeostatic situation, TNF triggers the formation of complex I, where RIPK1 (receptor interacting protein kinase 1) acts as a scaffold protein allowing the activation of the pro-inflammatory and protective pathway NF- κB (nuclear factor kappa-light-chain-enhancer of activated B cells). In pathologic conditions, complex IIa can be formed leading to the activation of caspase-8. Active caspase-8 cleaves RIPK1 and RIPK3 (receptor interacting protein kinase 3) and downstream caspases to induce apoptosis. Unlike complex IIa, complex IIb depends on the kinase role of RIPK1 to activate caspase-8 and execute apoptosis. Inhibition of RIPK1 kinase and ROS (reactive oxygen species) prevents this type of cell death. Finally, if caspases are inhibited and the NF- κB pathway is not activated, TNF can trigger the formation of the necrosome. This complex depends on the kinase activity of RIPK1 and RIPK3 to activate MLKL (mixed lineage kinase domain like). MLKL in turn will create the necroptotic pore in the plasma membrane inducing necroptosis, a regulated type of necrosis.