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

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 response1,2. 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 nucleus3,4,5,6,7,8,9. IKK kinase activity is stimulated when cells are exposed to the cytokine TNF-α 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-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.

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Figure 1: Aspirin inhibits NF-κB activation and IKK kinase activity.
Figure 2: Aspirin specifically inhibits IKK-β kinase activity.
Figure 3: Aspirin inhibits IKK-β kinase activity in vitro.
Figure 4: Aspirin and salicylate compete with ATP for binding to IKK-β.

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Acknowledgements

We thank F. Mercurio for IKK-α and IKK-β cDNAs, M. Cobb and E. Ross for discussion, and S. Johnson and E. Pasternack respectively for preparing the manuscript and figures. This work was supported by grants from the NIH, the Council for Tobacco Research and the Robert Welch Foundation.

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Correspondence to Richard B. Gaynor.

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Yin, MJ., Yamamoto, Y. & Gaynor, R. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β. Nature 396, 77–80 (1998). https://doi.org/10.1038/23948

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