Apoptosis: programmed cell death at a molecular level

Objectives: To characterize cell surface receptors, their ligands, and their proteins in the 2 major pathways of apoptosis; the components that promote/suppress these interactions; the noninflammatory removal of apoptotic bodies by dendritic cells; and methods of assay in studies of cell death. To describe: how deregulation of apoptosis may contribute to autoimmunity, cancer, and neurodegenerative disorders and strategies some viruses have evolved that interfere with the host's apoptotic pathways.

Methods: The authors reviewed and compiled literature on the extrinsic (tumor necrosis factor [TNF] receptor superfamily and ligands) and intrinsic (mitochondria-associated) apoptotic pathways, the pro- and antiapoptotic proteins of the B-cell follicular lymphoma (Bcl)-2 family, the nuclear factor (NF)-kappaB family of proteins, commonly used laboratory methods to distinguish apoptosis from necrosis, the recognition and removal by phagocytosis of apoptotic cells by dendritic cells, and viral strategies to avoid a host's apoptotic response.

Results: The 2 major pathways of apoptosis are (1). FasL and other TNF superfamily ligands induce trimerization of cell-surface death receptors and (2). perturbated mitochondria release cytochrome c, the flavoprotein apoptosis-inducing factor, and second mitochondria-derived activator of caspases/DIABLO (a protein that directly neutralizes inhibitors of apoptotic proteins and activates proteases). Catalytically inactive cysteine proteases, called caspases, and other proteases are activated, ultimately leading to cell death with characteristic cellular chromatin condensation and DNA cleavage to fragments of approximately 180 bp. The inhibitory/promoting action of Bcl-2 family members is involved in the release of cytochrome c, an essential factor for the mitochondrial-associated pathway. A balance between inhibition/promotion determines a cell's fate. The NF-kappaB family in the cytoplasm of cells activates various genes carrying the NF-kappaB response element, such as members of the inhibitor of apoptotic proteins family. A few of the more common methods to detect apoptotic cell death are described, which use immunochemical, morphologic and flow cytometric methods, and genetic markers. Exposed phosphatidylserine at the outer leaflet of the plasma membrane of the apoptotic cell serves as a possible receptor for phagocytosis by immature dendritic cells. These cells phagocytize both apoptotic and necrotic cells, but only the latter induce maturation to become fully functional antigen-presenting cells. Viral inhibitors of apoptosis allow increased virus replication in cells, possibly resulting in their oncogenicity.

Conclusions: Balanced apoptosis is crucial in development and homeostasis, and all multicellular organisms have a physiologically programmed continuum of pathways to apoptotic cell death. Further studies of the control at the molecular level of key components and promoters/suppressors of apoptosis may provide better approaches to treatment of autoimmune diseases, malignancies, and neurodegenerative disorders. Many important questions remain regarding the advantages of modifying apoptotic programs in clinical situations.