Isoacteoside, a dihydroxyphenylethyl glycoside, exhibits anti-inflammatory effects through blocking toll-like receptor 4 dimerization.

ABSTRACT: BACKGROUND AND PURPOSE:Isoacteoside (is a phenylethanoid isolated from Monochasma savatieri Franch. ex Maxim., which is an anti-inflammatory herb widely used in traditional Chinese medicine. However, the exact mechanism of the anti-inflammatory activity of isoacteoside is not completely understood. In this study, its anti-inflammatory mechanism was elucidated in mouse macrophages. EXPERIMENTAL APPROACH:The expression of the NF-?B pathway, MAPK pathway, iNOS, TNF-?, IL-6 and IL-1? was evaluated using Western blotting, quantitative real-time PCR or ELISA. TLR4 dimerization was determined by transfecting HEK293T cells with TLR4 plasmids. The in vivo anti-inflammatory effect of isoacteoside was determined using mouse models of xylene-induced ear oedema, LPS-induced endotoxic shock and LPS-induced endotoxaemia-associated acute kidney injury (AKI). KEY RESULTS:Isoacteoside suppressed COX-2, iNOS, TNF-?, IL-6 and IL-1? expression. Furthermore, isoacteoside attenuated the LPS-induced transcriptional activity of NF-?B by decreasing the levels of phosphorylated I?B-? and IKK and NF-?B/p65 nuclear translocation. In addition, isoacteoside inhibited LPS-induced transcriptional activity of AP-1 by reducing the levels of phosphorylated JNK1/2 and p38MAPK. Isoacteoside blocked LPS-induced TLR4 dimerization, resulting in a reduction in the recruitment of MyD88 and TIR-domain-containing adapter-inducing interferon-? (TRIF) and the phosphorylation of TGF-?-activated kinase-1 (TAK1). Pretreatment of mice with isoacteoside effectively inhibited xylene-induced ear oedema and LPS-induced endotoxic death and protected against LPS-induced AKI. CONCLUSIONS AND IMPLICATIONS:Isoacteoside blocked TLR4 dimerization, which activates the MyD88-TAK1-NF-?B/MAPK signalling cascades and TRIF pathway. Our data indicate that isoacteoside is a potential lead compound for the treatment of inflammatory diseases.

SUBMITTER: Gao H 

PROVIDER: S-EPMC5554315 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature