Mechanisms of IL-12 synthesis by human dendritic cells treated with the chemical sensitizer NiSO4.

Universud, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche S 749 and 996, Faculté de Pharmacie, Châtenay-Malabry, France.
The Journal of Immunology (Impact Factor: 5.52). 07/2010; 185(1):89-98. DOI: 10.4049/jimmunol.0901992
Source: PubMed

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 (NiSO(4)) 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 NiSO(4) stimulation. Addition of IFN-gamma concomitantly to NiSO(4) leads to IL-12p70 synthesis. NiSO(4) treatment leads to the activation of MAPK, NF-kappaB 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-kappaB pathways and RNA interference-mediated silencing of IRF-1. Our results showed that p38 MAPK, NF-kappaB, and IRF-1 were involved in IL-12p40 production induced by NiSO(4). Moreover, IRF-1 silencing nearly totally abrogated IL-12p40 and IL-12p70 production provoked by NiSO(4) and IFN-gamma. In response to NiSO(4), we observed that STAT-1 was phosphorylated on both serine and tyrosine residues and participated to NiSO(4)-induced IRF-1 activation. N-acetylcysteine abolished STAT-1 phosphorylation, suggesting that STAT-1 activation may be dependent on NiSO(4)-induced alteration of the redox status of the cell. These results indicate that p38 MAPK, NF-kappaB, and IRF-1 are activated by NiSO(4) in Mo-DC and cooperate for IL-12 production.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background/Purpose Monocytes play important roles in inflammatory responses and vascular remodeling after vascular stenting. This research focused on impacts of nickel (Ni) ions released from a corroded cardiovascular stent on cytotoxicity and monocyte activation. Methods A human promonocytic (macrophage-like) cell line (U937) was exposed to graduated concentrations of Ni2+in vitro. Cells were observed and harvested at indicated times to determine the effects using histological and biochemical methods. Results Ni caused U937 cell death in dose- and time-dependent manners. In vitro, high concentrations of Ni2+ (>240 μM) significantly induced cell apoptosis and increased terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling (TUNEL)-positive cells according to flow cytometric surveillance and triggered apoptotic cell death. Although no significant changes in Bcl-2 or Bax expressions were detected after 24 hours of Ni2+ treatment, increasing cleavage of caspase-3 and -8 was present. Results showed that cleavage of caspase-8 was inhibited by the presence of the inhibitor, Z-IETD-FMK, and this suggested the presence of Ni2+-induced U937 cell death through a death receptor-mediated pathway. Simultaneously, when treated with a high concentration of Ni2+ ions, expressions of the vascular remodeling factors, matrix metalloproteinases (MMP)-9 and -2, were activated in dose- and time-dependent manners. Secretion of the proliferative factor, monocyte chemoattractant protein (MCP)-1, significantly increased during the first 6 hours of incubation with 480 μM Ni2+-treated medium. Conclusion Our results demonstrated that a high concentration of Ni ions causes apoptotic cell death of circulating monocytes. They may also play different roles in vascular remodeling during the corrosion process following implantation of Ni alloy-containing devices.
    Journal of the Formosan Medical Association. 01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Contact sensitizers induce phenotypic and functional changes in dendritic cells (DC) that enhance their antigen-presenting capacity and, ultimately, modulate the T cell response. To evaluate if there is a similar effect of drugs causing T-cell-mediated cutaneous adverse drug reactions (CADR), we studied the in vitro effect of drugs on THP-1 cells, a cell line widely used to evaluate the early molecular and cellular events triggered by contact sensitizers. The effect of allopurinol, oxypurinol, ampicillin, amoxicillin, carbamazepine and sodium valproate, at EC30 concentrations, was evaluated on p38 MAPK activation, by Western Blot, and on the expression of genes coding for DC maturation markers, pro-inflammatory cytokine/chemokines and hemeoxygenase 1 (HMOX1), by real-time RT-PCR. Results were compared with lipopolysaccharide (LPS), a DC maturation stimulus, and the strong contact sensitizer, 1-fluoro-2,4-dinitrobenzene (DNFB). All drugs studied significantly upregulated HMOX1 gene transcription and all, except the anticonvulsants, also upregulated IL8. Allopurinol and oxypurinol showed the most intense effect, in a magnitude similar to DNFB and superior to betalactams. Transcription of CD40, IL12B and CXCL10 genes by drugs was more irregular. Moreover, like DNFB, all drugs activated p38 MAPK, although significantly only for oxypurinol. Like contact sensitizers, drugs that cause non-immediate CADR activate THP-1 cells in vitro, using different signalling pathways and affecting gene transcription with an intensity that may reflect the frequency and severity of the CADR they cause. Direct activation of antigen-presenting DC by systemic drugs may be an important early step in the pathophysiology of non-immediate CADR. Copyright © 2014 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 07/2014; · 2.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancers arising in mucosal tissues account for a disproportionately large fraction of malignancies. Immunoglobulin G (IgG) and the neonatal Fc receptor for IgG (FcRn) have an important function in the mucosal immune system that we have now shown extends to the induction of CD8(+) T cell-mediated antitumor immunity. We demonstrate that FcRn within dendritic cells (DCs) was critical for homeostatic activation of mucosal CD8(+) T cells that drove protection against the development of colorectal cancers and lung metastases. FcRn-mediated tumor protection was driven by DCs activation of endogenous tumor-reactive CD8(+) T cells via the cross-presentation of IgG complexed antigens (IgG IC), as well as the induction of cytotoxicity-promoting cytokine secretion, particularly interleukin-12, both of which were independently triggered by the FcRn-IgG IC interaction in murine and human DCs. FcRn thus has a primary role within mucosal tissues in activating local immune responses that are critical for priming efficient anti-tumor immunosurveillance.
    Immunity 11/2013; · 19.80 Impact Factor

Full-text (2 Sources)

Available from
May 15, 2014