Yin M J, Yamamoto Y, Gaynor R B
Department of Medicine, Harold Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas 75235-8594, USA.
Nature. 1998 Nov 5;396(6706):77-80. doi: 10.1038/23948.
NF-kappaB comprises a family of cellular transcription factors that are involved in the inducible expression of a variety of cellular genes that regulate the inflammatory response. NF-kappaB is sequestered in the cytoplasm by inhibitory proteins, I(kappa)B, which are phosphorylated by a cellular kinase complex known as IKK. IKK is made up of two kinases, IKK-alpha and IKK-beta, which phosphorylate I(kappa)B, leading to its degradation and translocation of NF-kappaB to the nucleus. IKK kinase activity is stimulated when cells are exposed to the cytokine TNF-alpha or by overexpression of the cellular kinases MEKK1 and NIK. Here we demonstrate that the anti-inflammatory agents aspirin and sodium salicylate specifically inhibit IKK-beta activity in vitro and in vivo. The mechanism of aspirin and sodium salicylate inhibition is due to binding of these agents to IKK-beta to reduce ATP binding. Our results indicate that the anti-inflammatory properties of aspirin and salicylate are mediated in part by their specific inhibition of IKK-beta, thereby preventing activation by NF-kappaB of genes involved in the pathogenesis of the inflammatory response.
核因子-κB（NF-κB）是一类细胞转录因子家族，参与多种调节炎症反应的细胞基因的诱导性表达。NF-κB被抑制蛋白IκB隔离于细胞质中，IκB可被一种称为IKK的细胞激酶复合物磷酸化。IKK由两种激酶IKK-α和IKK-β组成，它们使IκB磷酸化，导致其降解并使NF-κB转位至细胞核。当细胞暴露于细胞因子肿瘤坏死因子-α（TNF-α）或细胞激酶MEKK1和NIK过表达时，IKK激酶活性会受到刺激。在此我们证明，抗炎药物阿司匹林和水杨酸钠在体外和体内均能特异性抑制IKK-β活性。阿司匹林和水杨酸钠的抑制机制是由于这些药物与IKK-β结合以减少ATP结合。我们的结果表明，阿司匹林和水杨酸盐的抗炎特性部分是由它们对IKK-β的特异性抑制介导的，从而防止参与炎症反应发病机制的基因被NF-κB激活。
