Activation of nuclear factor-kappa B and gene expression in human endothelial cells by the common haptens nickel and cobalt.
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.
Goebeler
M
M
Institute of Experimental Dermatology, University of Münster, Germany.
Roth
J
J
Bröcker
E B
EB
Sorg
C
C
Schulze-Osthoff
K
K
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
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