1. Division of HematologyOncology, Department of Medicine, Harold Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8594, USA

Correspondence to: Richard B. Gaynor¹ Correspondence and requests for materials should be addressed to R.B.G. (e-mail: Email: gaynor@utsw.swmed.edu).

Abstract

NF-B comprises a family of cellular transcription factors that are involved in the inducible expression of a variety of cellular genes that regulate the inflammatory response¹,². NF-B is sequestered in the cytoplasm by inhibitory proteins, IB, which are phosphorylated by a cellular kinase complex known as IKK. IKK is made up of two kinases, IKK- and IKK-, which phosphorylate IB, leading to its degradation and translocation of NF-B to the nucleus^{3, 4, 5, 6, 7, 8, 9}. IKK kinase activity is stimulated when cells are exposed to the cytokine TNF- or by overexpression of the cellular kinases MEKK1 and NIK¹⁰,¹¹. Here we demonstrate that the anti-inflammatory agents aspirin and sodium salicylate specifically inhibit IKK- activity in vitro and in vivo. The mechanism of aspirin and sodium salicylate inhibition is due to binding of these agents to IKK- 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-, thereby preventing activation by NF-B of genes involved in the pathogenesis of the inflammatory response.