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Blood, 1 April 2005, Vol. 105, No. 7, pp. 2970-2972. Prepublished online as a Blood First Edition Paper on November 30, 2004; DOI 10.1182/blood-2004-07-2870. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-07-2870v1 105/7/2970    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cowburn, A. S. Articles by Chilvers, E. R. Search for Related Content PubMed PubMed Citation Articles by Cowburn, A. S. Articles by Chilvers, E. R. Related Collections Phagocytes Apoptosis Signal Transduction Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES Brief report z-VAD-fmk augmentation of TNF-stimulated neutrophil apoptosis is compound specific and does not involve the generation of reactive oxygen species Andrew S. Cowburn, Jessica F. White, John Deighton, Sarah R. Walmsley, and Edwin R. Chilvers From the Department of Medicine, University of Cambridge, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom. In most cell types constitutive and ligand-induced apoptosis is a caspase-dependent process. In neutrophils, however, the broad-spectrum caspase inhibitor z-VAD-fmk enhances tumor necrosis factor- (TNF)-induced cell death, and this has been interpreted as evidence for caspase-dependent and -independent cell death pathways. Our aim was to determine the specificity of the effect of z-VAD-fmk in neutrophils and define the potential mechanism of action. While confirming that z-VAD-fmk (> 100 µM) enhances TNF-induced neutrophil apoptosis, lower concentrations (1-30 µM) completely blocked TNF-stimulated apoptosis. Boc-D-fmk, a similar broad-spectrum caspase inhibitor, and z-IETD-fmk, a selective caspase-8 inhibitor, caused a concentration-dependent inhibition of only TNF-stimulated apoptosis. Moreover, the caspase-9 inhibitor, Ac-LEHD-cmk, had no effect on TNF-induced apoptosis, and z-VAD-fmk and Boc-D-fmk inhibited TNF-stimulated reactive oxygen species (ROS) generation. These data suggest that TNF-induced apoptosis in neutrophils is fully caspase dependent and uses a mitochondrial-independent pathway and that the proapoptotic effects of z-VAD-fmk are compound specific and ROS independent. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. R. Prince, S. M. Bianchi, K. M. Vaughan, M. A. Bewley, H. M. Marriott, S. R. Walmsley, G. W. Taylor, D. J. Buttle, I. Sabroe, D. H. Dockrell, et al. Subversion of a Lysosomal Pathway Regulating Neutrophil Apoptosis by a Major Bacterial Toxin, Pyocyanin J. Immunol., March 1, 2008; 180(5): 3502 - 3511. [Abstract] [Full Text] [PDF] A. Cross, R. J. Moots, and S. W. Edwards The dual effects of TNF{alpha} on neutrophil apoptosis are mediated via differential effects on expression of Mcl-1 and Bfl-1 Blood, January 15, 2008; 111(2): 878 - 884. [Abstract] [Full Text] [PDF] D. Zhu, H. Hattori, H. Jo, Y. Jia, K. K. Subramanian, F. Loison, J. You, Y. Le, M. Honczarenko, L. Silberstein, et al. Deactivation of phosphatidylinositol 3,4,5-trisphosphate/Akt signaling mediates neutrophil spontaneous death PNAS, October 3, 2006; 103(40): 14836 - 14841. [Abstract] [Full Text] [PDF] A. Daryadel, R. F. Grifone, H.-U. Simon, and S. Yousefi Apoptotic Neutrophils Release Macrophage Migration Inhibitory Factor upon Stimulation with Tumor Necrosis Factor-{alpha} J. Biol. Chem., September 15, 2006; 281(37): 27653 - 27661. [Abstract] [Full Text] [PDF] W. Martinet, G. R. Y. De Meyer, J.-P. Timmermans, A. G. Herman, and M. M. Kockx Macrophages but Not Smooth Muscle Cells Undergo Benzyloxycarbonyl-Val-Ala-DL-Asp(O-Methyl)-Fluoromethylketone-Induced Nonapoptotic Cell Death Depending on Receptor-Interacting Protein 1 Expression: Implications for the Stabilization of Macrophage-Rich Atherosclerotic Plaques J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1356 - 1364. [Abstract] [Full Text] [PDF] A. S. Cowburn, A. Sobolewski, B. J. Reed, J. Deighton, J. Murray, K. A. Cadwallader, J. R. Bradley, and E. R. Chilvers Aminopeptidase N (CD13) Regulates Tumor Necrosis Factor-{alpha}-induced Apoptosis in Human Neutrophils J. Biol. Chem., May 5, 2006; 281(18): 12458 - 12467. [Abstract] [Full Text] [PDF] M. Derouet, L. Thomas, D. A. Moulding, C. Akgul, A. Cross, R. J. Moots, and S. W. Edwards Sodium Salicylate Promotes Neutrophil Apoptosis by Stimulating Caspase-Dependent Turnover of Mcl-1 J. Immunol., January 15, 2006; 176(2): 957 - 965. [Abstract] [Full Text] [PDF]

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