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pubmed:abstractText |
Nickel chloride (NiCl2) and cobalt chloride (CoCl2), two haptens frequently leading to contact hypersensitivity in industrialized countries, induce gene transcription of adhesion molecules ICAM-1, VCAM-1, and E-selectin in endothelial cells. In search of transcriptional mechanisms underlying their gene-inductive effects, we studied the capacity of both haptens to activate nuclear factor (NF)-kappa B, a transcription factor involved in inducible expression of adhesion molecules. Using electrophoretic mobility shift assays, a strong increase of NF-kappa B DNA binding was detected after stimulation of HUVEC with NiCl2 or CoCl2. Supershift analysis using antisera against p50 and p65 confirmed the authenticity of the induced NF-kappa B complex. Neutralizing Abs against TNF-alpha and IL-1 did not inhibit metal hapten-induced activation of NF-kappa B, thus ruling out action via an indirect autocrine pathway. In addition, NiCl2-induced activation of NF-kappa B and adhesion molecule expression was inhibited by the antioxidant pyrrolidine dithiocarbamate, indicating the involvement of redox-dependent mechanisms. Furthermore, NiCl2 was found to induce dose-dependency mRNA production and protein secretion of the NF-kappa B-controlled proinflammatory cytokine IL-6. Our data suggest that distinct allergens represent a new class of so far unknown agents that induce NH-kappa B binding activity that subsequently modulates transcription of cytokine and adhesion molecule genes. Thus, pathomechanisms leading to contact hypersensitivity to NiCl2 and CoCl2 appear to involve not only Ag-specific Langerhans- and T cell-dependent events but also include direct effects on other immunocompetent cells such as the endothelium.
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