Yangonin Blocks Tumor Necrosis Factor-α–Induced Nuclear Factor-κB–Dependent Transcription by Inhibiting the Transactivation Potential of the RelA/p65 Subunit

• Published in: Journal of Pharmacological Sciences Vol. 118; no. 4; pp. 447 - 454
• Main Authors: Ma, Juan, Liang, He, Jin, Hong Ri, Dat, Nguyen Tien, Zhang, Shan Yu, Jiang, Ying Zi, Nan, Ji Xing, Li, Donghao, Wu, Xue, Lee, Jung Joon, Jin, Xuejun
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 2012; The Japanese Pharmacological Society; Elsevier
• Subjects: Animals; Dose-Response Relationship, Drug; HeLa Cells; Humans; inflammation; Mice; NF-kappa B - antagonists & inhibitors; NF-kappa B - physiology; nuclear factor-κB (NF-κB); Protein Subunits - antagonists & inhibitors; Protein Subunits - biosynthesis; Protein Subunits - genetics; Pyrones - chemistry; Pyrones - pharmacology; RelA/p65; transactivation; Transcription Factor RelA - antagonists & inhibitors; Transcription Factor RelA - biosynthesis; Transcription Factor RelA - genetics; Transcriptional Activation - drug effects; Transcriptional Activation - genetics; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; yangonin; yangonin; RelA/p65; inflammation; nuclear factor-κB (NF-κB); transactivation
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.11215FP

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 κBα (IκBα) 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 NH2-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.