The role of reactive oxygen intermediates in the regulation of cytokine-induced ICAM-1 surface expression on endothelial cells.
ICAM-1 upregulation by endothelial cells plays a pivotal role in many disease processes, but signalling mechanisms leading to increased expression are poorly understood. In the current study we investigated the regulatory capacity of reactive oxygen intermediates (ROIs) in ICAM-1 activation by stimulating endothelial cells with the pro-inflammatory cytokines IL-1 beta, TNF alpha, IFN gamma, IL-2, and IL-4 prior to antioxidant treatment. ICAM-1 was expressed constitutively and upregulated on ECV304 by IL1-beta, IL2, and IFN gamma and on SKHEP-1 by IFN gamma, IL1-beta, and TNF alpha. Phenanthroline (PHE) and disulfiram (DIS) showed the greatest ability to inhibit cytokine-stimulated ICAM-1 expression and in a dose-dependent manner. The alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) conversion assay showed that PHE and DIS had zero ability to scavenge free radicals and thus no known antioxidant activity. However, both are known metal chelators and our findings therefore suggest a unique role for metal ions in the control of cytokine-induced ICAM-1 expression on endothelial cells.
McMullen
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CB
Department of Microbiology and Immunobiology, Queen's University of Belfast, Royal Victoria Hospital, Grosvenor Road, Belfast, Northern Ireland, BT12 6BN, United Kingdom.n
Fleming
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E
Clarke
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Armstrong
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MA
D000975:Antioxidants / Q000494:pharmacology; D015764:Bepridil / Q000031:analogs & derivatives / Q000494:pharmacology; D001713:Biphenyl Compounds; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004221:Disulfiram / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010618:Phenanthrolines / Q000494:pharmacology; D010851:Picrates; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
D000975:Antioxidants; D001713:Biphenyl Compounds; D002614:Chelating Agents; D016207:Cytokines; D005609:Free Radicals; D007378:Interleukins; D010618:Phenanthrolines; D010851:Picrates; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D015764:Bepridil; D007371:Interferon-gamma; C004931:1,1-diphenyl-2-picrylhydrazyl; D004221:Disulfiram; C025205:1,10-phenanthroline