Abstract
As an attempt to search for bioactive natural products exerting anti-inflammatory activity, we have evaluated the anti-inflammatory effects of euscaphic acid (19α-hydroxyursane-type triterpenoids, EA) isolated from roots of Rosa rugosa and its underlying molecular mechanisms in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. EA concentration-dependently reduced the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) induced by LPS in RAW 264.7 macgophages. Consistent with these data, expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and iNOS, COX-2, TNF-α, and IL-1β mRNA were inhibited by EA in a concentration-dependent manner. In addition, EA attenuated LPS-induced DNA binding and transcriptional activity of nuclear factor-kappa B (NF-κB), which was accompanied by a parallel reduction of degradation and phosphorylation of inhibitory kappa Bα (IκBα) and consequently by decreased nuclear translocation of p65 subunit of NF-κB. Pretreatment with EA significantly inhibited the LPS-induced phosphorylation of IκB kinase β (IKKβ), p38, and JNK, whereas the phosphorylation of ERK1/2 was unaffected. Furthermore, EA interfered with the LPS-induced clustering of TNF receptor-associated factor 6 (TRAF6) with interleukin receptor associated kinase 1 (IRAK1) and transforming growth factor-β-activated kinase 1 (TAK1). Taken together, these results suggest that EA inhibits LPS-induced inflammatory responses by interference with the clustering of TRAF6 with IRAK1 and TAK1, resulting in blocking the activation of IKK and MAPKs signal transduction to downregulate NF-κB activations.
Copyright © 2012 Wiley Periodicals, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Cyclooxygenase 2 / biosynthesis
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Dinoprostone / biosynthesis
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Extracellular Signal-Regulated MAP Kinases / metabolism
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I-kappa B Proteins / metabolism
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Inflammation / drug therapy*
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Interleukin-1 Receptor-Associated Kinases / metabolism
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Interleukin-1beta / biosynthesis
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lipopolysaccharides / immunology
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MAP Kinase Kinase Kinases / metabolism
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MAP Kinase Signaling System / drug effects
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Macrophages / drug effects
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Macrophages / immunology*
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Macrophages / metabolism
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Mice
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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Nitric Oxide / biosynthesis
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Nitric Oxide Synthase Type II / biosynthesis
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Phosphorylation / drug effects
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Phytotherapy
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rosa / chemistry
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TNF Receptor-Associated Factor 6 / drug effects
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TNF Receptor-Associated Factor 6 / metabolism
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Toll-Like Receptor 4 / metabolism*
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Transcription Factor RelA / metabolism
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Transcription, Genetic / drug effects
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Triterpenes / pharmacology*
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Tumor Necrosis Factor-alpha / biosynthesis
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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I-kappa B Proteins
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Interleukin-1beta
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Lipopolysaccharides
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NF-kappa B
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Nfkbia protein, mouse
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RNA, Messenger
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Rela protein, mouse
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TNF Receptor-Associated Factor 6
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Transcription Factor RelA
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Triterpenes
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Nitric Oxide
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euscaphic acid
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Nitric Oxide Synthase Type II
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Cyclooxygenase 2
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Interleukin-1 Receptor-Associated Kinases
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Irak1 protein, mouse
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Dinoprostone