Glutathione depletion is associated with augmenting a proinflammatory signal: Evidence for an anti oxidant/pro-oxidant mechanism regulating cytokinesin the alveolar epithelium

Chemioxyexcitation [Delta pO(2)/reactive oxygen species (ROS)] constitutes a potential signaling mechanism for regulating an inflammatory signal assoc iated with oxidative stress. Exposure of fetal alveolar type II epithelial cells to an ascending Apo, regimen with or without the hydroxyl radical ((O H)-O-.) or the superoxide radical anion (O-2(-.)) induces a dose-dependent release of pro-inflammatory cytokines. Similarly, the Escherichia coli-deri ved lipopolysaccharide (LPS) upregulates cytokine biosynthesis in a dose- a nd time-dependent manner. Irreversible inhibition by L-buthionine-(S,R)-sul foximine (BSO) of gamma -glutamylcysteine synthetase, the rate-limiting enz yme in the biosynthesis of glutathione (GSH), induces intracellular accumul ation of ROS and augments chemioxyexcitation and LPS-mediated release of in terleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha). A nalysis of the molecular mechanism implicated reveals an inhibitory kappaB (I kappaB-alpha)/nuclear factor kappaB (NF-kappaB)-independent pathway medi ating the redox-dependent regulation of inflammatory cytokines. Although BS O stabilizes cytosolic I kappaB-alpha and downregulates its phosphorylation , thereby blockading NF-kappaB activation, it augments cytokine biosynthesi s in a dose-dependent manner. These results indicate that glutathione deple tion is associated with augmentation of an oxidative stress-mediated pro-in flammatory state in an ROS-dependent mechanism and that the I kappaB-alpha /NF-kappaB pathway is otherwise not necessarily indispensable for redox-med iated regulation of cytokines.