Glutathione redox regulates lipopolysaccharide-induced IL-12 production through p38 mitogen-activated protein kinase activation in human monocytes: role of glutathione redox in IFN-γ priming of IL-12 production

We examined whether changes in intracellular reduced (GSH) or oxidized (GSSG) glutathione of human monocytes regulate lipopolysaccharide (LPS)‐induced IL‐12 production and defined the molecular mechanism that underlies glutathione redox regulation. Monocytes exposed to glutathione reduced form ethyl ester (GSH‐OEt) or maleic acid diethyl ester (DEM) increased or decreased the intracellular GSH/GSSG ratio, respectively. LPS‐induced IL‐12 production and p38 mitogen‐activated protein (MAP) kinase activation were enhanced by GSH‐OEt but suppressed by DEM. Selective p38 inhibitors showed that p38 promoted GSH‐OEt‐enhanced IL‐12 production. Furthermore, IFN‐γ priming increased the GSH/GSSG ratio and enhanced IL‐12 production through p38, and DEM negated the priming effect of IFN‐γ on p38 activation and IL‐12 production as well as on the GSH/GSSG ratio. These findings reveal that glutathione redox regulates LPS‐induced IL‐12 production from monocytes through p38 MAP kinase activation and that the priming effect of IFN‐γ on IL‐12 production is partly a result of the glutathione redox balance.