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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2001-12-0266. This Article Full Text (PDF) All Versions of this Article: 2001-12-0266v1 101/1/295    most recent Alert me when this article is cited Alert me if a correction is posted 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 Liu, C.-Y. Articles by Chuang, P. I Search for Related Content PubMed PubMed Citation Articles by Liu, C.-Y. Articles by Chuang, P. I Social Bookmarking                   What's this? Submitted December 18, 2001 Accepted June 5, 2002 Broad-spectrum caspase inhibition paradoxically augments cell death in TNF-stimulated neutrophils Chien-Ying Liu, Akihiro Takemasa, W Conrad Liles, Richard B Goodman, Mechthild Jonas, Henry Rosen, Emil Chi, Robert K Winn, John M Harlan, and Peter I Chuang* Department of Medicine, University of Washington, Seattle, WA, USA Department of Pathology, University of Washington, Seattle, WA, USA Department of Surgery, University of Washington, Seattle, WA, USA * Corresponding author; email: ichuang{at}u.washington.edu. It is increasingly clear that there are caspase -dependent and -independent mechanisms for the execution of cell death and that the utilization of these mechanisms is stimulus- and cell-type- dependent. Intriguingly, broad-spectrum caspase inhibition enhances death receptor agonist-induced cell death in a few transformed cell lines. Endogenously produced oxidants are causally linked to necrotic-like cell death in these instances. We report here that broad-spectrum caspase inhibitors effectively attenuated apoptosis induced in human neutrophils by incubation with agonistic anti-Fas antibody or by coincubation with TNF and cycloheximide ex vivo. Nevertheless, the same caspase inhibitors could augment cell death upon stimulation by TNF alone during the 6-hour time-course examined. Caspase inhibitor-sensitized, TNF-stimulated, dying neutrophils exhibit apoptotic-like and necrotic-like features. This occurred without apparent alteration in NF-B activation. Nevertheless, intracellular oxidant production was enhanced and sustained in caspase inhibitor-sensitized, TNF-stimulated neutrophils obtained from normal subjects. However, despite reduced or absent intracellular oxidant production following TNF-stimulation, cell death was also augmented in neutrophils isolated from patients with chronic granulomatous disease incubated with a caspase inhibitor and TNF. These results demonstrate that, in human neutrophils, TNF induces a caspase-independent but protein synthesis-dependent cell death signal. Furthermore, they suggest that TNF activates a caspase-dependent pathway that negatively regulates NADPH oxidase activity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Biragyn, M. Coscia, K. Nagashima, M. Sanford, H. A. Young, and P. Olkhanud Murine {beta}-defensin 2 promotes TLR-4/MyD88-mediated and NF-{kappa}B-dependent atypical death of APCs via activation of TNFR2 J. Leukoc. Biol., April 1, 2008; 83(4): 998 - 1008. [Abstract] [Full Text] [PDF] D. Shan, R. B. Marchase, and J. C. 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