title: Desmethylanhydroicaritin inhibits NF-kappaB-regulated inflammatory gene expression by modulating the redox-sensitive PI3K/PTEN/Akt pathway.
abstract: We investigated the effect of desmethylanhydroicaritin (DMAI), a major compound of the Chinese herbal medicine Epimedium, on inflammatory gene expression and the NF-kappaB signaling pathway. We found that DMAI suppressed the expression of NF-kappaB-responsive genes, such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1beta, and tumor necrosis factor-alpha, in lipopolysaccharide (LPS)-stimulated macrophages and endotoxemic mice as well as protected mice against LPS-induced lethality. DMAI inhibited NF-kappaB activation through the inhibition of IkappaB kinase (IKK) activation, IkappaB phosphorylation and degradation, and NF-kappaB 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 H(2)O(2) 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-kappaB activation in macrophages treated with H(2)O(2). These results indicate that DMAI negatively regulates canonical NF-kappaB-regulated inflammatory gene expression by functioning as an inhibitor of the NF-kappaB pathway through the suppression of redox-based PI3K activation and PTEN inactivation and therefore can be considered as a potential drug for inflammatory diseases.
authors.affiliation: Vascular System Research Center, Kangwon National University, Chuncheon, Republic of Korea.
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Gwangsoo
authors.initials: G
authors.lastname: Lee
authors.forename: Young-Lai
authors.initials: YL
authors.lastname: Cho
authors.forename: Chun-Ki
authors.initials: CK
authors.lastname: Kim
authors.forename: Sanghwa
authors.initials: S
authors.lastname: Han
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.forename: Jae Sue
authors.initials: JS
authors.lastname: Choi
authors.forename: Jongseon
authors.initials: J
authors.lastname: Choe
authors.forename: Moo-Ho
authors.initials: MH
authors.lastname: Won
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.forename: Kwon-Soo
authors.initials: KS
authors.lastname: Ha
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
mesh_terms: D000818:Animals; D002460:Cell Line; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D047309:Flavones / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047309:Flavones; D008070:Lipopolysaccharides; D016328:NF-kappa B; C539396:desmethylanhydroicaritin; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase