Activation of nuclear factor κB as a target for antiinflammatory therapy

Abstract

NF-κB 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-κB is sequestered in the cytoplasm by inhibitory proteins, IκB, which are phosphorylated by a cellular kinase complex known as IKK. IKK is made up of two kinases, IKK-α and IKK-β, which phosphorylate IκB, leading to its degradation and translocation of NF-κB to the nucleus. IKK kinase activity is stimulated when cells are exposed to the cytokine TNF-α 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-β activity in vitro and in vivo. The mechanism of aspirin and sodium salicylate inhibition is due to binding of these agents to IKK-β 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-β, thereby preventing activation by NF- κB of genes involved in the pathogenesis of the inflammatory response.