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

Ursolic acid, which was isolate from an ethanol extract of Cornus officinalis seed, potently inhibited nuclear factor kappa light-chain enhancer of activated Bcells (NF-kappa B) 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 kappa B kinase subunit beta (IKK beta), and I kappa B alpha as well as activation of NF-kappa B and MAPKs in LPS-stimulated macrophages. Ursolic acid suppressed LPS-stimulated interleukin (IL)-1 beta, IL-6, tumor necrosis factor (TNF)-alpha, 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 teh macrophages transiently transfected with or without MyD88 siRNA However, ursolic acid did not suppress NF-kappa B activation in peptidoglycan-stimulated macrophages. Oral administration of ursolic acid significanly inhibited 2,4,6-trinitrobenzenesulfonic acids (TNBS)-induced colon shortening and myeloperoxidas (MPO) activity in mice. Ursolic acid also suppresed TNBS induced COX-2 and iNOS expression as well as NF-kappa B activation in colon tissues. Ursolic acid (20 mg/kg) also inhibited TNBS induced IL-1 beta, IL-6, TNF-alpha by 93,86, and 85%, respectively (p < .005). However, ursolic acid reversed TNBS-mediated downregulation of IL-10 expression to 79% of the normal control group (p < 0.005). On the basis of these findings, ursolic acid may ameliorate colitis by regulating NF-kappa B and MAPK signaling pathways via the inhibiton of LPS binding to TLR4 on immune cells.