Yangonin blocks tumor necrosis factor-α-induced nuclear factor-κB-dependent transcription by inhibiting the transactivation potential of the RelA/p65 subunit.

Abstract

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 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.

• Authors: Juan Ma, He Liang, Hong Ri Jin, Nguyen Tien Dat, Shan Yu Zhang, Ying Zi Jiang, Ji Xing Nan, Donghao Li, Xue Wu, Jung Joon Lee, Xuejun Jin
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 118 Issue 4 Pg. 447-54 ( 2012) ISSN: 1347-8648 [Electronic] Japan
• PMID: 22510965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Protein Subunits
• Pyrones
• Transcription Factor RelA
• Tumor Necrosis Factor-alpha
• yangonin

Topics

• Animals
• Dose-Response Relationship, Drug
• HeLa Cells
• Humans
• Mice
• NF-kappa B (antagonists & inhibitors, physiology)
• Protein Subunits (antagonists & inhibitors, biosynthesis, genetics)
• Pyrones (chemistry, pharmacology)
• Transcription Factor RelA (antagonists & inhibitors, biosynthesis, genetics)
• Transcriptional Activation (drug effects, genetics)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, biosynthesis, genetics)