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

Abstract: Tumor necrosis factor- (TNF-)-acti-vated neutrophils phagocytose and eliminate bac-teria by using such oxidants as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), which is produced from H2O2 by myeloperoxidase (MPO). Thereafter, neutrophils eventually undergo apo-ptosis to prevent excessive inflammation. How-ever, 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 inhib-itory protein short form (FLIPS) was specifically down-regulated by TauCl. TNF-/TauCl cotreat-ment-induced apoptosis was largely blocked by sta-ble expression of FLIPS. Cotreatment with TNF- and H2O2 promoted apoptotic signaling via MPO activation and subsequent attenuation of FLIPS ex-pression. TNF- priming with H2O2 or bacteria caused MPO-dependent apoptosis in human neu-trophils. However, FLIPS 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, oxi-dization 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 an-tiapoptotic signaling induced by TNF- via NF-B activation can be altered to promote apoptosis via H2O2-MPO-mediated FLIPS down-regulation an