Redox Imbalance Induced by Contact Sensitizers Triggers the Maturation of Dendritic Cells

Abstract

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.

Signal transduction profile of chemical sensitisers in dendritic cells: An endpoint to be included in a cell-based in vitro alternative approach to hazard identification?

“…In previous results performed with the foetal skin-derived dendritic cell line (FSDC), we reported that DNFB activates p38 MAPK and ERK1/2 via the production of reactive oxygen species and that protein oxidation plays an important role in MAPKs activation (Matos et al, 2005b). These results are in agreement with the key role of oxidative stress in the activation of MAPKs (Mizuashi et al, 2005;Hirota et al, 2009;Suzuki et al, 2009;Kagatani et al, 2010).…”

Effect of lipopolysaccharide, skin sensitizers and irritants on thioredoxin-1 expression in dendritic cells: relevance of different signalling pathways

“…It was also demonstrated that the redox imbalance induced by skin sensitizers is important in the regulation of DC functions [5,38,39,41,47,61]. Therefore, the increase in Trx-1 mRNA expression observed in .…”

“…Similarly to LPS, skin sensitizers can induce redox imbalance [38,41] that activates the cellular mechanism proposed above and responsible for the increase in Trx-1 protein levels. These data suggest that the ASK1/Nrf2/ ARE regulatory pathway could be activated by LPS and skin sensitizers in a similar way, being involved in DC maturation.…”

Sulfamethoxazole and Its Metabolite Nitroso Sulfamethoxazole Stimulate Dendritic Cell Costimulatory Signaling

“…It is known that dendritic cell maturation signals can also be provided by necrotic cell death through the release of intracellular molecules into the extracellular matrix (27,28), apoptotic cell death (29), or the induction of oxidative stress (30,31). Indeed, studies with contact sensitizers have demonstrated that small protein-reactive compounds can induce dendritic cell maturation (30,32,33) at concentrations associated with significant cell death (34).…”