title: Ursolic acid isolated from the seed of Cornus officinalis ameliorates colitis in mice by inhibiting the binding of lipopolysaccharide to Toll-like receptor 4 on macrophages.
abstract: Ursolic acid, which was isolated from an ethanol extract of Cornus officinalis seed, potently inhibited nuclear factor κ light-chain enhancer of activated B cells (NF-κB) activation in lipopolysaccharide (LPS)-stimulated peritoneal macrophages. Therefore, we investigated the anti-inflammatory mechanism of ursolic acid in LPS-stimulated macrophages and colitic mice. Ursolic acid inhibited phosphorylation of interleukin 1 receptor-associated kinase (IRAK)1, TAK1, inhibitor of nuclear factor κB kinase subunit β (IKKβ), and IκBα as well as activation of NF-κB and MAPKs in LPS-stimulated macrophages. Ursolic acid suppressed LPS-stimulated interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and inducible NO synthetase (iNOS) expression as well as PGE2 and NO levels. Ursolic acid not only inhibited the Alexa Fluor 488-conjugated LPS-mediated shift of macrophages but also reduced the intensity of fluorescent LPS bound to the macrophages transiently transfected with or without MyD88 siRNA. However, ursolic acid did not suppress NF-κB activation in peptidoglycan-stimulated macrophages. Oral administration of ursolic acid significantly inhibited 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colon shortening and myeloperoxidase (MPO) activity in mice. Ursolic acid also suppressed TNBS-induced COX-2 and iNOS expression as well as NF-κB activation in colon tissues. Ursolic acid (20 mg/kg) also inhibited TNBS-induced IL-1β, IL-6, TNF-α by 93, 86, and 85%, respectively (p < 0.05). However, ursolic acid reversed TNBS-mediated downregulation of IL-10 expression to 79% of the normal control group (p < 0.05). On the basis of these findings, ursolic acid may ameliorate colitis by regulating NF-κB and MAPK signaling pathways via the inhibition of LPS binding to TLR4 on immune cells.
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, ‡Department of Food and Nutrition, and §Department of Pharmacy, Kyung Hee University , Seoul 130-701, Korea.
authors.forename: Se-Eun
authors.initials: SE
authors.lastname: Jang
authors.forename: Jin-Ju
authors.initials: JJ
authors.lastname: Jeong
authors.forename: Supriya R
authors.initials: SR
authors.lastname: Hyam
authors.forename: Myung Joo
authors.initials: MJ
authors.lastname: Han
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D029768:Cornus / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology; D012639:Seeds / Q000737:chemistry; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010457:Peptidoglycan; D051197:Toll-Like Receptor 4; D014302:Trinitrobenzenesulfonic Acid; D014315:Triterpenes; D000097245:Ursolic Acid; C493487:Tlr4 protein, mouse
keywords: Cornus officinalis; colitis; macrophage; toll-like receptor 4; ursolic acid