title: Activation of nuclear factor-kappa B and gene expression in human endothelial cells by the common haptens nickel and cobalt.
abstract: 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.
authors.affiliation: Institute of Experimental Dermatology, University of Münster, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Goebeler
authors.forename: J
authors.initials: J
authors.lastname: Roth
authors.forename: E B
authors.initials: EB
authors.lastname: Bröcker
authors.forename: C
authors.initials: C
authors.lastname: Sorg
authors.forename: K
authors.initials: K
authors.lastname: Schulze-Osthoff
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002478:Cells, Cultured; D003035:Cobalt / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology; D019040:E-Selectin; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006241:Haptens / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics*; D009532:Nickel / Q000276:immunology; D011759:Pyrrolidines / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: D000975:Antioxidants; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D006241:Haptens; D015850:Interleukin-6; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C020972:pyrrolidine dithiocarbamic acid; D003035:Cobalt; C022838:nickel chloride; D009532:Nickel; C018021:cobaltous chloride