Published online before print August 20, 2007

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(Journal of Leukocyte Biology. 2007;82:1344-1352.)
© 2007 by Society for Leukocyte Biology

Apoptosis triggered by phagocytosis-related oxidative stress through FLIP_S down-regulation and JNK activation

Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba Japan

¹ Correspondence: Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Bioscience Building 402, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan. E-mail: kanayama-atsuhiro{at}k.u-tokyo.ac.jp

Tumor necrosis factor- (TNF-)-activated neutrophils phagocytose and eliminate bacteria by using such oxidants as hydrogen peroxide (H₂O₂) and hypochlorous acid (HOCl), which is produced from H₂O₂ by myeloperoxidase (MPO). Thereafter, neutrophils eventually undergo apoptosis to prevent excessive inflammation. However, it is unclear how this process is regulated. Here, we show that cotreatment of TNF--resistant neutrophilic HL-60 cells with taurine chloramine (TauCl), a detoxified form of HOCl, and TNF- renders them susceptible to apoptosis, mostly by preventing nuclear factor-B (NF-B) activation. Of several NF-B target genes tested, FLICE inhibitory protein short form (FLIP_S) was specifically down-regulated by TauCl. TNF-/TauCl cotreatment-induced apoptosis was largely blocked by stable expression of FLIP_S. Cotreatment with TNF- and H₂O₂ promoted apoptotic signaling via MPO activation and subsequent attenuation of FLIP_S expression. TNF- priming with H₂O₂ or bacteria caused MPO-dependent apoptosis in human neutrophils. However, FLIP_S knock-down by siRNA did not affect the viability of cells treated with TNF-, implying that TauCl may affect another pathway in TNF--driven apoptosis. Indeed, oxidization of thioredoxin-1 (Trx-1) by TauCl induced the activation of apoptosis signal-regulating kinase 1 (ASK1) and cJun N-terminal kinase (JNK), thereby triggering TNF--mediated apoptosis. Taken together, these results indicate that the antiapoptotic signaling induced by TNF- via NF-B activation can be altered to promote apoptosis via H₂O₂-MPO-mediated FLIP_S down-regulation and JNK activation.

Key Words: taurine chloramine • ASK1 • TNF

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