Licochalcone A Potently Inhibits Tumor Necrosis Factor α-Induced Nuclear Factor-κB Activation through the Direct Inhibition of IκB Kinase Complex Activation

Glycyrrhiza inflata has been used as a traditional medicine with anti-inflammatory activity; however, its mechanism has not been fully understood. Licochalcone A is a major and biogenetically characteristic chalcone isolated from G. inflata. Here, we found that licochalcone A strongly inhibited tumor necrosis (TNF)-alpha-induced nuclear localization, DNA binding activity, and the transcriptional activity of nuclear factor-kappa B (NF-kappa B). Whereas licochalcone A had no effect on the recruitment of receptor-interacting protein 1 and I kappa B kinase beta (IKK beta) to TNF receptor I by TNF-alpha, it significantly inhibited TNF-alpha-induced I kappa B kinase complex (IKK) activation and inhibitor of nuclear factor-kappa B degradation. It is interesting that we found that the cysteine residue at position 179 of IKK beta is essential for licochalcone A-induced IKK inhibition, because licochalcone A failed to affect the kinase activity of the IKK beta (C179A) mutant. In contrast, a structurally related compound, echinatin, failed to inhibit TNF-alpha-induced IKK activation and NF-kappa B activation, suggesting that the 1,1-dimethy-2-propenyl group in licochalcone A is important for the inhibition of NF-kappa B. In addition, TNF-alpha-induced expression of inflammatory cytokines CCL2/monocyte chemotactic protein-1 and CXCL1/KC was clearly inhibited by licochalcone A but not echinatin. Taken together, licochalcone A might contribute to the potent anti-inflammatory effect of G. inflata through the inhibition of IKK activation.