Licochalcone A potently inhibits tumor necrosis factor alpha-induced nuclear factor-kappaB activation through the direct inhibition of IkappaB 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-kappaB (NF-kappaB). Whereas licochalcone A had no effect on the recruitment of receptor-interacting protein 1 and IkappaB kinase beta (IKKbeta) to TNF receptor I by TNF-alpha, it significantly inhibited TNF-alpha-induced IkappaB kinase complex (IKK) activation and inhibitor of nuclear factor-kappaB degradation. It is interesting that we found that the cysteine residue at position 179 of IKKbeta is essential for licochalcone A-induced IKK inhibition, because licochalcone A failed to affect the kinase activity of the IKKbeta (C179A) mutant. In contrast, a structurally related compound, echinatin, failed to inhibit TNF-alpha-induced IKK activation and NF-kappaB activation, suggesting that the 1,1-dimethy-2-propenyl group in licochalcone A is important for the inhibition of NF-kappaB. In addition, TNF-alpha-induced expression of inflammatory cytokines CCL2/monocyte chemotactic protein-1and 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.