Apoptosis Inducing Cytokines

TNF Family

Members of the TNF family can regulate apoptosis in addition to an array of other biological effects such as cell proliferation and differentiation. TNF family ligands mediate death in susceptible target cells by interacting with their cell surface bound TNF family death receptors. Despite the functional redundancy of this family, specificity may be accomplished by coordinating the spatial and temporal expression of TNF-related ligands and their receptors and by restricting the expression of signal transduction molecules to specific cell types.

Interferons (IFNs)

Induction of cell death or apoptosis was not initially considered an action of IFNs. However, in vitro IFNα and IFNγ induced changes in morphology of cells such as detachment of cells characteristic of apoptotic cells in multiple cells lines which led to the identification of activation of the caspase cascade. IFNs are now considered as apoptosis inducing cytokines.

Regardless of cell type or tissue histology, induction of apoptosis by all IFN subtypes has involved FADD/caspase-8 signaling, activation of the caspase cascade, release of cytochrome c from mitochondria, disruption of mitochondrial potential, changes in plasma membrane symmetry and DNA fragmention.

In addition to inducing tumor cell apoptosis, IFNs mya exert anti-tumor effects by augmenting cytotoxic T cells, natural killer cells (NKs) and DCs. For example, IFNα , IFNΒ and IFN-γ stimulated DCs expressed TRAIL and induced apoptosis of target cells. Cytotoxicity mediated by IFN stimulated DCs led to activation of caspase-3 and NF-kB in target cells. Thus IFNs may trigger DCs to induce apoptosis of the target cells, resulting in subsequent uptake and processing of apoptotic bodies and presentation of antigenic peptides to CD8+ cytotoxic lymphocytes.

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