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

Tumor necrosis factor-alpha (TNF-alpha)-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-alpha-resistant neutrophilic HL-60 cells with taurine chloramine (TauCl), a detoxified form of HOCl, and TNF-alpha renders them susceptible to apoptosis, mostly by preventing nuclear factor-kappa B (NF-kappa B) activation. Of several NF-kappa B target genes tested, FLICE inhibitory protein short form (FLIPS) was specifically down-regulated by TauCl. TNF-alpha/TauCl cotreatment-induced apoptosis was largely blocked by stable expression of FLIPS. Cotreatment with TNF-alpha and H(2)O(2)promoted apoptotic signaling via MPO activation and subsequent attenuation of FLIPS expression. TNF-alpha priming with H2O2 or bacteria caused MPO-dependent apoptosis in human neutrophils. However, FLIPS knock-down by siRNA did not affect the viability of cells treated with TNF-alpha, implying that TanCl may affect another pathway in TNF-alpha-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-alpha-mediated apoptosis. Taken together, these results indicate that the antiapoptotic signaling induced by TNF-alpha via NF-kappa B activation can be altered to promote apoptosis via H2O2-MPO-mediated FLIPS down-regulation and JNK activation.