Ambient but not incremental oxidant generation effects intercellular adhesion molecule 1 induction by tumour necrosis factor alpha in endothelium.
Proinflammatory cytokines upregulate endothelial adhesion molecule expression, thereby initiating the microvascular inflammatory response. We re-evaluated the reported role of reactive oxygen metabolites (ROMs) in signalling upregulation of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells by tumour necrosis factor alpha (TNF-alpha) in vitro. TNF-alpha upregulation of endothelial-cell ICAM-1 expression was inhibited by the cell-permeable antioxidants, or by the adenovirus-mediated intracellular overexpression of Cu,Zn-superoxide dismutase, but not by the exogenous (extracellular) administration of the cell-impermeable antioxidants, superoxide dismutase and/or catalase. This ICAM-1 upregulation was also inhibited by inhibitors of NADH dehydrogenase, cytochrome bc1 complex and NADPH oxidase. However, a measurable increase in net cellular ROM generation in response to TNF-alpha was not seen using four disparate sensitive ROM assays. Moreover, the stimulation of exogenous or endogenous ROM generation did not upregulate ICAM-1, nor enhance ICAM-1 upregulation by TNF-alpha. These findings suggest that an ambient background flux of ROMs, generated intracellularly, but not their net incremental generation, is necessary for TNF-alpha to induce ICAM-1 expression in endothelium in vitro.
Arai
T
T
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4685, USA.
Kelly
S A
SA
Brengman
M L
ML
Takano
M
M
Smith
E H
EH
Goldschmidt-Clermont
P J
PJ
Bulkley
G B
GB
D000256:Adenoviridae / Q000201:enzymology / Q000235:genetics; D000975:Antioxidants / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006825:Hybridomas / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000502:physiology
D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D013482:Superoxide Dismutase; D009245:NADH Dehydrogenase