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

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-κB) signaling in cells and experimental murine colitis. 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-α (TNF-α) 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-κB signaling was examined by immunoblot analysis to detect IκBα phosphorylation/degradation and electrophoretic mobility shift assay to assess the DNA binding activity of NF-κB. 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 IκBα was performed in the colonic tissue. UA significantly inhibited the production of pro-inflammatory cytokines, IκBα phosphorylation/degradation and NF-κB DNA binding activity in both IEC and IL-10(-/-) peritoneal macrophages stimulated with TNF-α and 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 IκBα phosphorylation in the colonic tissue. UA inhibits NF-κB 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.