Caffeoylquinic acids isolated from Lonicera japonica Thunb. as TAK1 inhibitors protects against LPS plus IFN-γ-stimulated inflammation by interacting with KEAP1-regulated NRF2 activation.

The transforming growth factor-β-activated kinase 1 (TAK1) phosphorylation promotes inflammation occurrence. Meanwhile, TAK1 directly interacts with KEAP1 and strenghtenes NRF2/HO-1 pathway downregulated-inflammation. Recently, we found that caffeoylquinic acids not only possessed powderful anti-inflammation function, but also attenuated oxidative damage through KEAP1/NRF2 pathway. Whereas it's rarely understood whether the anti-inflammatory activity were regulated by their interaction between TAK1 and NRF2. Herein, 34 caffeoylquinic acids including five new (2, 4-7) were systematically isolated and identified on the basis of spectroscopic evidence from Lonicera japonica Thunb. flower buds. Their inhibitory effects on inflammation induced by LPS plus IFN-γ were exerted substantial NO scavenging activity, and inhibited massive production of inflammatory cytokines and related proteins. Compound 3 (4F5C-QAME) exhibited the best anti-inflammation activity. 4F5C-QAME down-regulated the phosphorylation of TAK1, JNK, and c-JUN, thereby alleviated inflammation stimulated by LPS plus IFN-γ. Meanwhile, 4F5C-QAME could alleviate the interaction between TAK1 and KEAP1, inhibit the ubiquitination degradation of NRF2, activate NRF2/HO-1 signaling pathway, result in the increase in ROS elimination. Furthermore, 4F5C-QAME effectively protected against inflammation through direct inhibition of TAK1 phosphorylation. Based on these findings, 4F5C-QAME directly targeting TAK1 could be represented as a potential drug candidate for preventing/treating inflammatory diseases that regulated NRF2 activation through alleviating the interaction between TAK1 and KEAP1. Moreover, the regulatory mechanism of TAK1 on NRF2 activation under exogenous oxidative stress was revealed for the first time.