Desmethylanhydroicaritin inhibits NF-κB-regulated inflammatory gene expression by modulating the redox-sensitive PI3K/PTEN/Akt pathway

Ji Hee Kim, Gwangsoo Lee, Young Lai Cho, Chun Ki Kim, Sanghwa Han, Hansoo Lee, Jae Sue Choi, Jongseon Choe, Moo Ho Won, Young Guen Kwon, Kwon Soo Ha, Young Myeong Kim

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Abstract

We investigated the effect of desmethylanhydroicaritin (DMAI), a major compound of the Chinese herbal medicine Epimedium, on inflammatory gene expression and the NF-κB signaling pathway. We found that DMAI suppressed the expression of NF-κB-responsive genes, such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1β, and tumor necrosis factor-α, in lipopolysaccharide (LPS)-stimulated macrophages and endotoxemic mice as well as protected mice against LPS-induced lethality. DMAI inhibited NF-κB activation through the inhibition of IκB kinase (IKK) activation, IκB phosphorylation and degradation, and NF-κB nuclear translocation in LPS-stimulated macrophages. This compound inhibited in vitro and in vivo LPS-induced phosphatidylinositol 3-kinase (PI3K) activation, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) oxidation, and Akt phosphorylation, which are upstream modulators of IKK activation. Moreover, treatment with DMAI was not observed to affect the interaction between the Toll-like receptor 4, MyD88, and TRAF6 as well as mitogen-activated protein kinase activation. DMAI also suppressed intracellular H2O2 accumulation, hydroxyl radical production, and glutathione oxidation without affecting superoxide generation and accumulation by NADPH oxidase. Moreover, DMAI inhibited redox-sensitive activation of the PI3K/PTEN/Akt pathway and NF-κB activation in macrophages treated with H2O2. These results indicate that DMAI negatively regulates canonical NF-κB-regulated inflammatory gene expression by functioning as an inhibitor of the NF-κB pathway through the suppression of redox-based PI3K activation and PTEN inactivation and therefore can be considered as a potential drug for inflammatory diseases.

Original languageEnglish
Pages (from-to)422-431
Number of pages10
JournalEuropean Journal of Pharmacology
Volume602
Issue number2-3
DOIs
Publication statusPublished - 2009 Jan 14

All Science Journal Classification (ASJC) codes

  • Pharmacology

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    Kim, J. H., Lee, G., Cho, Y. L., Kim, C. K., Han, S., Lee, H., Choi, J. S., Choe, J., Won, M. H., Kwon, Y. G., Ha, K. S., & Kim, Y. M. (2009). Desmethylanhydroicaritin inhibits NF-κB-regulated inflammatory gene expression by modulating the redox-sensitive PI3K/PTEN/Akt pathway. European Journal of Pharmacology, 602(2-3), 422-431. https://doi.org/10.1016/j.ejphar.2008.10.062