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

摘要

Ursolic acid, which was isolated from an ethanol extract of Cornus officinalis seed, potently inhibited nuclear factor K light-chain enhancer of activated B cells (NF-kB) 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 kB kinase subunit β (IKKβ), and IkBα as well as activation of NF-kB 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-kB activation in peptidoglycan-stimulated macrophages. Oral administration of ursolic add 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-kB activation in colon tissues.