4′,6-Dihydroxy-4-methoxyisoaurone inhibits TNF-α-induced NF-κB activation and expressions of NF-κB-regulated target gene products

The nuclear factor-κb (nf-κb) transcription factors control many physiological processes including inflammation,apoptosis,and angiogenesis. in our search for nf-κb inhibitors from natural resources,we identified 4′,6-dihydroxy-4-methoxyisoaurone (isoa) as an inhibitor of nf-κb activation from the seeds of trichosanthes kirilowii. however,the mechanism by which isoa inhibits nf-κb activation is not fully understood. in the present study,we demonstrated the effect of isoa on nf-κb activation in tnf-α-stimulated hela cells. this compound suppressed nf-κb activation through the inhibition of iκb kinase (ikk) activation. isoa also has an influence on upstream signaling of ikk through the inhibition of expression of adaptor proteins,tnf receptor-associated factor 2 (traf2) and receptor interacting protein 1 (rip1). consequently,isoa blocked the phosphorylation and degradation of the inhibitor of nf-κb alpha (iκbα),and subsequent phosphorylation and nuclear translocation of p65. the suppression of nf-κb activation by isoa led to the down-regulation of target genes involved in inflammation,proliferation,as well as potentiation of tnf-α-induced apoptosis. taken together,this study extends our understanding on the mechanisms underlying the anti-inflammatory and anti-cancer activities of isoa. our findings provide new insight into the molecular mechanisms and a potential application of isoa for inflammatory diseases as well as certain cancers. © 2015 the authors. production and hosting by elsevier b.v. on behalf of japanese pharmacological society.