Extrinsic/receptor-mediated pathway

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

The extrinsic pathway of apoptosis or the death receptor-mediated pathway is activated at the cell surface when a specific ligand binds to its corresponding cell-surface death receptor viz. TNF receptor, TNF-related... 

Figure 1 Schematic representation of the receptor-mediated (extrinsic) and the intracellular stress-mediated (intrinsic) pathways of caspase activation. Death-receptor signaling may involve direct caspase-8-mediated caspase-3 activation (type 1 cells) ora Bid-cleavage-dependent mitochondrial amplification step (type 2 cells).

Apoptosis (programmed cell death) is a genetically controlled cell suicide process that has an essential role for the maintenance of homeostasis and prevention of cancer and some other diseases substantially in all living cells [141], Apoptosis is an optional elimination method for irreversibly damaged cells. The two major pathways that initiate apoptosis are extrinsic (death receptor mediated) and intrinsic (mitochondrial mediated). In addition, mitogenic and stress-responsive pathways are involved in the regulation of apoptotic signaling [142],... 

Fig. 13.1 Schematic of Apoptosis Components Affected by Ethanoi Five generai eiements of apoptotic pathways in neurons have been shown to be impacted by ethanoi. They tire iiiustrated by the block arrows. There are two basic pathways that have been reported to be activated by ethanoi, extrinsic receptor activation and intrinsic mitochondrialiy mediated pathways. In general, developmental exposure to ethanol shifts expression of Bcl-2 family proteins in a pro apoptotic direction which may be mechanistically connected to the observed enhanced mitochondrial release of cytochrome c (cyto c) and apoptosis inducing factor (AIF). These factors, in turn, likely play roles in the subsequent activation of the effector caspase-3 (cytochrome c) and DNA fragmentation (AIF) (See also Color Insert)...

Figure 14-8. Overview of pathways that regulate programmed cell death. Apoptosis may occur in response to signaling through either the extrinsic pathway or the intrinsic pathway. In each case, proteolytic cleavage activates an initiator caspase, caspase 8 or 9, either of which can cleave an effector caspase such as caspase 3. Apaf-1 is part of a large complex called the apoptosome that mediates the intrinsic pathway. Binding of an extracellular death ligand to its cell-surface receptor activates the extrinsic pathway.

TNF is a cytokine produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF TNF-Rl and TNF-R2. The binding of TNF to TNF-Rl has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain (TRADD) and Fas-associated death domain (FADD). The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially autoimmune diseases (see Chapter 15). 

Figure 1. Schematic of the apoplotic signaling pathways. The intrinsic apoptotic pathway consists of the mitochondrial pathway. The extrinsic pathway mediates apoptosis through activation of the death receptors, TNF-o/Fas receptors. Apoptosis is executed by activation of proteases, known as caspascs. ATP is essential for apoptosis. Bel-2 family proteins are apoptosis regulating proteins Bcl-2 inhibits while Bid, Bax, Bad facilitate apoptosis. An interaction between these two apoptotic pathways exists. See text for a more detailed explanation.

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