RRC ID 43729
Author Honda H, Nagai Y, Matsunaga T, Saitoh S, Akashi-Takamura S, Hayashi H, Fujii I, Miyake K, Muraguchi A, Takatsu K.
Title Glycyrrhizin and isoliquiritigenin suppress the LPS sensor toll-like receptor 4/MD-2 complex signaling in a different manner.
Journal J Leukoc Biol
Abstract Recent evidences suggest that the extracts of plant products are able to modulate innate immune responses. A saponin GL and a chalcone ILG are representative components of Glycyrrhiza uralensis, which attenuate inflammatory responses mediated by TLRs. Here, we show that GL and ILG suppress different steps of the LPS sensor TLR4/MD-2 complex signaling at the receptor level. Extract of G. uralensis suppressed IL-6 and TNF-α production induced by lipid A moiety of LPS in RAW264.7 cells. Among various G. uralensis-related components of saponins and flavanones/chalcones, GL and ILG could suppress IL-6 production induced by lipid A in dose-dependent manners in RAW264.7 cells. Furthermore, elevation of plasma TNF-α in LPS-injected mice was attenuated by passive administration of GL or ILG. GL and ILG inhibited lipid A-induced NF-κB activation in Ba/F3 cells expressing TLR4/MD-2 and CD14 and BMMs. These components also inhibited activation of MAPKs, including JNK, p38, and ERK in BMMs. In addition, GL and ILG inhibited NF-κB activation and IL-6 production induced by paclitaxel, a nonbacterial TLR4 ligand. Interestingly, GL attenuated the formation of the LPS-TLR4/MD-2 complexes, resulting in inhibition of homodimerization of TLR4. Although ILG did not affect LPS binding to TLR4/MD-2, it could inhibit LPS-induced TLR4 homodimerization. These results imply that GL and ILG modulate the TLR4/MD-2 complex at the receptor level, leading to suppress LPS-induced activation of signaling cascades and cytokine production, but their effects are exerted at different steps of TLR4/MD-2 signaling.
Volume 91(6)
Pages 967-76
Published 2012-6-1
DOI 10.1189/jlb.0112038
PII jlb.0112038
PMID 22422925
MeSH Animals Anti-Inflammatory Agents / chemistry Anti-Inflammatory Agents / pharmacology* Cell Line Chalcones / chemistry Chalcones / pharmacology* Enzyme Inhibitors / chemistry Enzyme Inhibitors / pharmacology* Glycyrrhiza uralensis / chemistry Glycyrrhizic Acid / chemistry Glycyrrhizic Acid / pharmacology* Interleukin-6 / immunology Interleukin-6 / metabolism Lipopolysaccharide Receptors / immunology Lipopolysaccharide Receptors / metabolism Lipopolysaccharides / pharmacology* Lymphocyte Antigen 96 / immunology* Lymphocyte Antigen 96 / metabolism MAP Kinase Signaling System / drug effects* MAP Kinase Signaling System / immunology Mice Mice, Inbred BALB C Mitogen-Activated Protein Kinase Kinases / immunology Mitogen-Activated Protein Kinase Kinases / metabolism NF-kappa B / immunology NF-kappa B / metabolism Protein Multimerization / drug effects Protein Multimerization / immunology Toll-Like Receptor 4 / immunology* Toll-Like Receptor 4 / metabolism Tumor Necrosis Factor-alpha / immunology Tumor Necrosis Factor-alpha / metabolism
IF 3.757
Times Cited 53
Human and Animal Cells RAW 264(RCB0535)