Mechanisms of IL-12 Synthesis by Human Dendritic Cells Treated with the Chemical Sensitizer NiSO4

Abstract

Allergic contact dermatitis, caused by metallic ions, is a T cell-mediated inflammatory skin disease. IL-12 is a 70-kDa heterodimeric protein composed of IL-12p40 and IL-12p35, playing a major role in the generation of allergen-specific T cell responses. Dendritic cells (DCs) are APCs involved in the induction of primary immune responses, as they possess the ability to stimulate naive T cells. In this study, we address the question whether the sensitizer nickel sulfate (NiSO4) itself or in synergy with other signals can induce the secretion of IL-12p70 in human monocyte-derived DCs (Mo-DCs). We found that IL-12p40 was produced by Mo-DC in response to NiSO4 stimulation. Addition of IFN-γ concomitantly to NiSO4 leads to IL-12p70 synthesis. NiSO4 treatment leads to the activation of MAPK, NF-κB pathways, and IFN regulatory factor 1 (IRF-1). We investigated the role of these signaling pathways in IL-12 production using known pharmacological inhibitors of MAPK and NF-κB pathways and RNA interference-mediated silencing of IRF-1. Our results showed that p38 MAPK, NF-κB, and IRF-1 were involved in IL-12p40 production induced by NiSO4. Moreover, IRF-1 silencing nearly totally abrogated IL-12p40 and IL-12p70 production provoked by NiSO4 and IFN-γ. In response to NiSO4, we observed that STAT-1 was phosphorylated on both serine and tyrosine residues and participated to NiSO4-induced IRF-1 activation. N-acetylcysteine abolished STAT-1 phosphorylation, suggesting that STAT-1 activation may be dependent on NiSO4-induced alteration of the redox status of the cell. These results indicate that p38 MAPK, NF-κB, and IRF-1 are activated by NiSO4 in Mo-DC and cooperate for IL-12 production.

Keratinocytes, Innate Immunity and Allergic Contact Dermatitis - Opportunities for the Development of In Vitro Assays to Predict the Sensitizing Potential of Chemicals

“…Similar results were obtained in an experiment using the monocytic THP-1 cell line (Mitjans et al, 2010). These signaling pathways are essential for the further maturation of dendritic cells and the activation of hapten-specific T cells, since they trigger the production of cytokines such as TNF- IL-6, IL-12 and IL-18 in keratinocytes or dendritic cells and are essential in the upregulation of costimulatory molecules on the surface of the dendritic cells (Antonios et al, 2009;Antonios et al, 2010). …”

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?

“…Furthermore, p38 MAPK, NF-kB and IRF-1 were involved in nickel-induced IL-12p40 production in human monocyte-derived DC (Antonios et al, 2010). Taken together, these data indicate that although some sensitisers activate the NF-kB transcription factor and are probably responsible for some phenotypic modifications observed in DC, other sensitisers failed to activate this signalling pathway.…”

“…However, the authors used short incubation periods (15 min) and it could be speculated that although contact allergens did not directly activate JAK/STAT, an effect on this signalling pathway may be observed with longer incubation times, which corresponds to an autocrine effect of cytokines released by DC in response to sensitisers. Recent studies also showed that NiSO 4 induces STAT1 phosphorylation on serine and tyrosine residues that participate in NiSO 4 -induced IRF-1 activation in human dendritic cells (Antonios et al, 2010). However, the authors used longer incubation periods (2 to 4 h).…”

“…The results showed that both NiSO 4 and CoCl 2 activate similar signalling pathways that play different roles in DC maturation, depending on the hapten used. Recent studies also showed that p38 MAPK is activated by NiSO 4 in human monocytederived DC and cooperates for IL-12 production (Antonios et al, 2010). In human CD34 + -derived DC, nickel activates p38 MAPK, ERK1/2 and JNK, all of which are MAPKs involved in the expression of CD83, CD86 and CCR7 but not in the nickel-induced down-regulation of E-cadherin and Langerin (Boisleve et al, 2005).…”

Nickel Ion Inhibits Nuclear Factor-Kappa B Activity in Human Oral Squamous Cell Carcinoma

“…The biological effects of Ni 2+ ions have been studied in several distinct cell types such as monocytes [26] [27] [28] [29], dendritic cells [30] [31], endothelial cells [28], [32] and epithelial cells [33] [34]. Although most of these studies demonstrated enhanced secretion of soluble factors or expression of cell adhesion molecules, inhibitory effects have also been demonstrated in different experimental settings [26] [27].…”