The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β

Abstract

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.

Therapeutic effects of acetylsalicylic acid in giant cell arteritis

“…Initial observations indicate that ASA prevented the phosphorylation and degradation of I B␣, causing cytoplasmic trapping of NF-B (19,20). Yin et al (33) have recently reported that the inhibitory effect of ASA resulted from the specific inhibition of ATP binding to I K␤. As a consequence, phosphorylation of I B␣ was markedly reduced, which prevented its degradation and activation of the NF-B pathway.…”

Inflammation and insulin resistance

“…While they are somewhat effective in achieving glucose control at high doses, side effects, such as gastrointestinal bleeding and tinnitus, prevent their widespread use [28]. These compounds are relatively weak inhibitors of Ikkb, thus preventing Irs1 serine307 phosphorylation and this presumably accounts for their insulin-sensitizing effects [29]. Several approaches have been used to demonstrate IkkbÕs direct involvement in diet-induced chronic inflammation and insulin action.…”

Inhibitors of NF-κB signaling: 785 and counting

“…Aspirin is commonly thought to act pharmacologically primarily via inhibition of prostaglandin synthesis (Weissmann, 1991). However, at higher concentrations, aspirin has also been shown to block NF-kB activity by directly binding to and inhibiting the kinase activity of IKKb by reducing its ability to bind ATP (Yin et al, 1998); more recently, aspirin has also been reported to inhibit proteasome activity and consequently to interfere with degradation of IkB (Dikshit et al, 2006). As such, high-dose aspirin therapy may have applications to diseases where NF-kB activity is involved, including cancer (McCarty and Block, 2006), diabetes (Yuan et al, 2001) and heart disease (Li and Fang, 2004).…”