Glycyrrhizin, the main active compound in licorice, attenuates pro-inflammatory responses by interfering with membrane-dependent receptor signaling.

Biochem J. 2009 May 14; Schröfelbauer B, Raffetseder J, Hauner M, Wolkerstorfer A, Ernst W, Szolar OHThe triterpene glycoside glycyrrhizin (GL) is the main active compound in licorice. It is used as a herbal medicine owing to its anti-cancer, anti-viral, and anti-inflammatory properties. Its mode of action however remains widely unknown. In this study, we aimed to elucidate the molecular mechanism of GL in attenuating inflammatory responses in macrophages. Using microarray analysis, we found that GL caused a broad block in the induction of pro-inflammatory mediators induced by the toll-like receptor 9 (TLR9) agonist CpG-DNA in RAW 264.7 cells. Furthermore, we found that GL also strongly attenuated inflammatory responses induced by TLR3 and TLR4 ligands. The inhibition was accompanied by reduced activation not only of the NF-kappaB pathway but also of the parallel MAPKs signaling cascade upon stimulation with TLR9 and TLR4 agonists. Further analysis of upstream events revealed that GL treatment reduced cellular attachment and/or uptake of CpG-DNA and strongly impaired TLR4 internalization. Moreover, we found that the anti-inflammatory effects were specific for membrane-dependent receptormediated stimuli, as GL was ineffective in blocking Tnfa induction upon stimulation with phorbol myristate acetate (PMA), a receptor and membrane-independent stimulus. These observations suggest that the broad anti-inflammatory activity of GL is mediated by the interaction with the lipid bilayer thereby attenuating receptor-mediated signaling.