Redox regulation of pyo-inflammatory cytokines and IκB-α/NF-κB nuclear translocation and activation

被引:132
作者
Haddad, JJ [1 ]
机构
[1] Univ Calif San Francisco, Sch Med, Dept Anesthesia & Perioperat Care, Serveringhaus Res Labs,Mol Neurosci Res Div, San Francisco, CA 94143 USA
基金
美国国家卫生研究院;
关键词
antioxidant; chemioxyexcitation; cytokines; glutathione disequilibrium; pharmacotherapy; reactive oxygen species; redox/thiol regulation;
D O I
10.1016/S0006-291X(02)00947-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Reduction-oxidation (redox) state constitutes such a potential signaling mechanism for the regulation of an inflammatory signal associated with oxidative stress. Exposure of alveolar epithelial cells to ascending DeltapO(2) regimen +/-reactive oxygen species (ROS)-generating systems induced a dose-dependent release of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. Similarly, the Escherichia coli-derived lipopolysaccharide-endotoxin (LPS) up-regulated cytokine biosynthesis in a dose- and time-dependent manner. Irreversible inhibition of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of glutathione (GSH), by L-buthionine-(SR)-sulfoximine (BSO), induced the accumulation of ROS and augmented DeltapO(2) and LPS-mediated release of cytokines. Analysis of the molecular mechanism implicated revealed an inhibitory-kappaB (IkappaB-alpha)/nuclear factor-kappaB (NF-kappaB)-independent pathway in mediating redox-dependent regulation of inflammatory cytokines. BSO stabilized cytosolic IkappaB-alpha and down-regulated its phosphorylation, thereby blockading NF-kappaB activation, yet it augmented cytokine secretion. Glutathione depletion is associated with the augmentation of oxidative stress-mediated inflammatory state in a ROS-dependent mechanism and the IkappaB-alpha/NF-kappaB pathway is redox-sensitive but differentially involved in regulating redox-dependent regulation of cytokines. (C) 2002 Elsevier Science (USA). All rights reserved.
引用
收藏
页码:847 / 856
页数:10
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