Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 174, Issue 17, Pages 2880-2896Publisher
WILEY
DOI: 10.1111/bph.13912
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Funding
- Science and Technology Development Fund, Macao S.A.R (FDCT) [078/2016/A2]
- Research Fund from University of Macau [MYRG2016-00043-ICMS-QRCM]
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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-kappa B pathway, MAPK pathway, iNOS, TNF-alpha, IL-6 and IL-1 beta 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-alpha, IL-6 and IL-1 beta expression. Furthermore, isoacteoside attenuated the LPS-induced transcriptional activity of NF-kappa B by decreasing the levels of phosphorylated I kappa B-alpha and IKK and NF-kappa 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 TIRdomain- containing adapter-inducing interferon-beta (TRIF) and the phosphorylation of TGF-beta-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-kappa B/MAPK signalling cascades and TRIF pathway. Our data indicate that isoacteoside is a potential lead compound for the treatment of inflammatory diseases.
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