Figure 5

Schematic diagram of NF-κB activation circuits and oxygen-signaling mechanisms. Reduction of oxidized glutathione (GSSG) to glutathione (GSH), which is blocked by 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), leads to increasing intracellular stores of GSSG, a potent inhibitor of NF-κB transcription factor DNA binding. The pathway leading to the formation of GSH by the action of γ-glutamylcysteine synthetase (GCS) is blocked by L-buthionine-(S,R)-sulfoximine (BSO), inducing an irreversible inhibition of NF-κB activation. Reactive oxygen species (ROS) are key components of the pathways leading to the activation of NF-κB, whose binding activity is obliterated by N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), potent scavengers of ROS. Although NAC is elevating reduced GSH, it is unknown whether this mechanism induces NF-κB activation independently from the antioxidant effects of this inhibitor. PDTC elevates GSSG concentration by GSH oxidation, a pro-oxidant effect characteristic of dithiocarbamates, thereby mediating NF-κB inhibition. Upon NF-κB DNA binding, cascades of hyperoxia-responsive genes are activated, which have the potential to modulate cellular response to oxidative injury. ROOH, highly reactive peroxide.