The nuclear factor-
κB (NF-
κB) transcription factors control many physiological processes including inflammation, immunity, and apoptosis. In our search for NF-
κB inhibitors from natural resources, we identified yangonin from
Piper methysticum as an inhibitor of NF-
κB activation. In the present study, we demonstrate that yangonin potently inhibits NF-
κB activation through suppression of the transcriptional activity of the RelA/p65 subunit of NF-
κB. This compound significantly inhibited the induced expression of the NF-
κB-reporter gene. However, this compound did not interfere with tumor necrosis factor-
α (TNF-
α)-induced inhibitor of
κB
α (I
κB
α) degradation, p65 nuclear translocation, and DNA-binding activity of NF-
κB. Further analysis revealed that yangonin inhibited not only the induced NF-
κB activation by overexpression of RelA/p65, but also transactivation activity of RelA/p65. Moreover, yangonin did not inhibit TNF-
α-induced activation of p38, but it significantly impaired activation of extracellular signal-regulated kinase 1/2 and stress-activated protein kinase/c-Jun NH
2-terminal kinase. We also demonstrated that pretreatment of cells with this compound prevented TNF-
α-induced expression of NF-
κB target genes, such as interleukin 6, interleukin 8, monocyte chemotactic protein 1, cyclooxygenase-2 and inducible nitric oxide. Taken together, yangonin could be a valuable candidate for the intervention of NF-
κB-dependent pathological conditions such as inflammation.
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