Regulation and measurement of oxidative stress in apoptosis

NF-κB meets ROS: an ‘iron-ic’ encounter

“…18 However, most prior studies dealing with this issue have measured TNF-R-triggered ROS production at relatively late times (i.e. several hours), 14,15,18 and so these measurements were likely affected by the oxidative burst that invariably follows mitochondrial outer membrane depolarization, 2 an event often signifying that cells have already committed to die. 2 Thus, whether mitochondrial generation of ROS is a cause or an effect of cell death remains unclear.…”

“…20 The FHC-mediated inhibition of PCD induced by TNFa involves suppressing the induction of ROS and thereby sustained activation of JNK signaling. 14 This action of FHC depends on sequestration of free iron 14 -a metal that catalyzes generation of ROS in mitochondria and through Fenton and HaberWeiss reactions, 18,20 resulting in formation of highly reactive hydroxyl ( K OH) radicals. 18,20 Interestingly, knockdown experiments suggest that, in some tissues, FHC might represent a dominant component of the protective mechanism activated by NF-kB for inhibiting TNF-R-induced PCD.…”

“…14 This action of FHC depends on sequestration of free iron 14 -a metal that catalyzes generation of ROS in mitochondria and through Fenton and HaberWeiss reactions, 18,20 resulting in formation of highly reactive hydroxyl ( K OH) radicals. 18,20 Interestingly, knockdown experiments suggest that, in some tissues, FHC might represent a dominant component of the protective mechanism activated by NF-kB for inhibiting TNF-R-induced PCD. 14 Notably, FHC is one of several acute-phase proteins, upregulated in the liver during the organismal response to stress, injury and infection, 20 and so, might mediate a systemic cytoprotective mechanism activated by NF-kB during chronic inflammation, when the potential exists for extensive ROS-mediated, tissue damage.…”

“…[3][4][5] Studies by other laboratories had previously shown that the protective activity of NF-kB against ROS-inflicted damage is also mediated by upregulation of the antioxidant enzyme, Mn-SOD 4 -which catalyzes dismutation of superoxide anion ( K O 2 À) into hydrogen peroxide (H 2 O 2 ). 4,18 Interestingly, whereas in some contexts Mn-SOD is likely to be an important element for NF-kB-mediated suppression of PCD, 4 its ectopic expression seems to afford little or no protection against TNFa-induced cytotoxicity in NF-kB-deficient cells. 14,15 Hence, while required for controlling TNFa-prompted changes in redox status, Mn-SOD alone does not appear to be sufficient to mediate the ROS-inhibiting and protective functions of NF-kB.…”

“…It is plausible that whereas induction of Mn-SOD promotes dismutation of K O 2 À into H 2 O 2 , FHC-mediated iron depletion might be required to enable disposal of H 2 O 2 by catalases and peroxidases. 14,18 Bases for the NF-jB-mediated control of the JNK cascade Combined upregulation of FHC and Mn-SOD provides a basis for the antioxidant activity of NF-kB. It also provides an indirect link between the NF-kB and JNK pathways (Figure 1).…”