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作者机构:NYU Sch Med Dept Microbiol New York NY 10016 USA
出 版 物:《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)
年 卷 期:2000年第275卷第15期
页 面:10925-10929页
核心收录:
学科分类:0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学]
基 金:NCI NIH HHS [R35-CA49731, R01-CA75071] Funding Source: Medline NIGMS NIH HHS [5T32-GM07308] Funding Source: Medline
主 题:COS细胞 钙-钙调素依赖性蛋白激酶类/拮抗剂和抑制剂 I-κB蛋白质类/拮抗剂和抑制剂 咪唑类/药理学 白细胞介素1/药理学 丝裂原激活蛋白激酶类 吡啶类/药理学 水杨酸钠/药理学 肿瘤坏死因子α/药理学 p38丝裂原活化蛋白激酶类 动物 人类
摘 要:Sodium salicylate inhibits activation of the transcription factor NF-kappa B by blocking the phosphorylation and degradation of the NF-kappa B inhibitor I kappa B alpha. We previously demonstrated that salicylate inhibits I kappa B alpha degradation induced by tumor necrosis factor (TNF) but not by interleukin-1 (IL-1) and implicated p38 mitogen-activated protein kinase activation by salicylate in the inhibition of TNF-induced I kappa B alpha phosphorylation. Both TNF and IL-1 rapidly activate the I kappa B kinase (IKK) complex, containing the catalytic subunits IKK alpha and IKK beta, which directly phosphorylates I kappa B proteins. Others have recently suggested that salicylate inhibits NF-kappa B activation by directly binding to IKK beta. To clarify the mechanism whereby salicylate inhibits IKK activity, we examined its effects upon cytokine-induced IKK activity in intact cells and in vitro, Treatment of intact cells with salicylate inhibited TNF-induced but not IL-1-induced IKK activity, and this inhibition was prevented by the p38 inhibitor SB203580. In contrast, inhibition of IKK activity by salicylate in vitro was neither selective for TNF nor affected by SB203580. In vitro, salicylate treatment comparably inhibited the kinase activity of overexpressed IKK alpha and IKK beta and also decreased p38 kinase activity. Therefore, direct inhibition of IRK activity in vitro does not reflect the inhibitory mechanism of salicylate in intact cells, which involves interference with TNF signaling.