Tumor necrosis factor-α induces a caspase-independent death pathway in human neutrophils

Blood, 101, 1987-1995, 2003

Speaker : 李建勳                   Time : 5 NOV 2003 ;pm 1:00~2:00

Commentator : 謝奇璋醫師                         Place : Room 601

Abstract

    Tumor necrosis factorα (TNF-α) is a cytokine released by macrophages and some other cells, and involves in certain inflammatory diseases, such as rheumatoid arthritis.  TNF-α induces apoptosis while ligating to the TNF receptors; conversely, it also triggers a pathway that leads to survival (1, 2).  Neutrophils are short-lived but most abundant in circulation responsible for inflammatory reactions.  TNF-α-induced apoptosis could be completely inhibited by zVAD-fmk, the pan caspase inhibitor.  However, such treatment could not rescue PMNs from death because the combination of TNF-α and zVAD-fmk leads to an atypical cell death.  TNF-α/zVAD-fmk-induced cell death lacks classical features of apoptosis, such as chromatin condensation, DNA laddering, and Bax redistribution (3).  On the other hand, TNF-α/zVAD-fmk treated cells are enlarged and nuclei are hyperlobulated.  The TNF-α/zVAD-fmk-induced cell death in cytoplasts (which lack mitochondria) or PMNs from CGD patients (chronic granulomatous disease, with impaired NADPH oxidase system) cytoplasts (which lack mitochondria) results from mitochondria-derived ROS release.  Such kind of cell death is later defined as necrosis-like programmed cell death, which is cause by over release of ROS that leads to mitochondrial dysfunction and other cellular injuries(4).  Therefore, TNF-α could trigger a typical caspases-involved apoptosis and a caspase-independent, necrosis-like cell death.

References

1.      Olivier M. & Jürg T. Induction of TNF Receptor I-Mediated Apoptosis via Two Sequential Signaling Complexes. Cell, 114, 181–190, 2003,

2.      Bharat A. Signaling pathways of the TNF superfamily: A double-edged sword. Nat. Rev. Immunol., 3, 745-756, 2003

3.      Nikolai M., et al. Tumor necrosis factorα induces a caspase-independent death pathway in human neutrophils. Blood, 101, 1987-1995, 2003