Ursolic acid inhibits nuclear factor-κB signaling in intestinal epithelial cells and macrophages, and attenuates experimental colitis in mice

Aims: Ursolic acid (UA), a natural pentacyclic triterpenoid acid, has been reported to show immunomodulatory activity. This study investigated the effects of UA on nuclear factor-kappa B (NF-kappa B) signaling in cells and experimental murine colitis. Main methods: Human intestinal epithelial cells (IECs) COLO 205 and peritoneal macrophages from IL-10-deficient (IL-10(-/-)) mice were pretreated with UA and then stimulated with tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS), respectively. The expression of pro-inflammatory cytokines was determined by real-time RT-PCR and ELISA. The effect of UA on NF-kappa B signaling was examined by immunoblot analysis to detect I kappa B alpha phosphorylation/ degradation and electrophoretic mobility shift assay to assess the DNA binding activity of NF-kappa B. For in vivo studies, dextran sulfate sodium (DSS)-induced acute colitis in C57BL/6 wild-type mice and chronic colitis in IL-10(-/-) mice were treated with or without UA. Colitis was quantified by histopathologic evaluation. Immunohistochemical staining for phosphorylated I kappa B alpha was performed in the colonic tissue. Key findings: UA significantly inhibited the production of pro-inflammatory cytokines, I kappa B alpha phosphorylation/degradation and NF-kappa B DNA binding activity in both IEC and IL-10(-/-) peritoneal macrophages stimulated with TNF-alpha aand LPS, respectively. UA significantly reduced the severity of DSS-induced murine colitis, as assessed by the disease activity index, colon length, and histopathology. UA also significantly ameliorated the severity of colitis in IL-10(-/-) mice. Furthermore, UA suppressed I kappa B alpha phosphorylation in the colonic tissue. Significance: UA inhibits NF-kappa B activation in both IECs and macrophages, and attenuates experimental murine colitis. These results suggest that UA is a potential therapeutic agent for inflammatory bowel disease. (C) 2014 Elsevier Inc. All rights reserved.