Article date: September 2017
By: Hongwei Gao, Yankun Cui, Naixin Kang, Xin Liu, Yanli Liu, Yue Zou, Ziyu Zhang, Xiaoran Li, Shilin Yang, Ji Li, Chunming Wang, Qiong‐ming Xu, Xiuping Chen in Volume 174, Issue 17, pages 2880-2896
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‐κB pathway, MAPK pathway, iNOS, TNF‐α, IL‐6 and IL‐1β 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‐α, IL‐6 and IL‐1β expression. Furthermore, isoacteoside attenuated the LPS‐induced transcriptional activity of NF‐κB by decreasing the levels of phosphorylated IκB‐α and IKK and NF‐κB/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‐β (TRIF) and the phosphorylation of TGF‐β‐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‐κB/MAPK signalling cascades and TRIF pathway. Our data indicate that isoacteoside is a potential lead compound for the treatment of inflammatory diseases.
DOI: 10.1111/bph.13912
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