Redox imbalance induced by contact sensitizers triggers the maturation of dendritic cells

Although p38 mitogen-activated protein kinases (MAPK) play a crucial role in the activation of monocyte-derived dendritic cells (MoDC) by contact sensitizers, the upstream signals of p38 MAPK remain undetermined. To examine whether sensitizers induce redox or oxidative stress in dendritic cells (DC), which subsequently stimulate p38 MAPK, we measured the ratio of the oxidized (GSSG) versus reduced (GSH) form of cellular glutathione in MoDC stimulated with five sensitizers including NiCl2 and 2,4-dinitrochlorobenzene (DNCB) and three non-sensitizers including sodium dodecyl sulfate using colorimetric assays. All the sensitizers, but none of the non-sensitizers at sublethal concentration, reduced the GSH/GSSG ratio, which was accompanied by phosphorylation of p38 MAPK. Treatment with the antioxidant, N-acetyl-l-cysteine, which suppressed the reduction of the GSH/GSSG ratio, abrogated both the phosphorylation of p38 MAPK and the augmentation of CD86 expression. A similar response pattern was observed in THP-1 macrophage-monocyte cells. Unexpectedly, however, formaldehyde (HCHO) reduced the GSH/GSSG ratio in MoDC, but not in THP-1. This finding, in conjunction with the observation that DNCB and NiCl2 reduced the GSH/GSSG ratio at different kinetics, indicated that the sensitizers reduced the GSH/GSSG ratio by a different mechanism. These data suggest that the GSH/GSSG imbalance plays a crucial role in triggering DC maturation by sensitizers.