Background: Lupeol, a natural pentacyclic triterpene, is shown to anti-infl ammatory effect but its role in colitis has not been investigated. This study evaluated the effects of lupeol on the p38-MAPK/NF-κB signaling pathways and on experimental colitis. Methods: The human intestinal epithelial cell (IEC)-line COLO 205 and the murine macrophage cell-line RAW264.7 were prepared and subsequently stimulated with lipopolysaccharide (LPS) alone or LPS plus various dose of lupeol. The secretion of IL-8from COLO 205 cell-line was measured by ELISA and the productions of TNF-a, IL-6 and IL-12 from RAW 264.7 cell-line were also qualifi ed by ELISA. The effects of lupeol on IκBa and p38-MAPK phosphorylation, which regulate the production of pro-in- fl ammatory cytokines, were examined by western blotting. In in vivo studies, dextran sulfate sodium (DSS)-induced acute colitis in wild-type mice and chronic colitis in IL- 10-/- mice were treated with or without lupeol. Colitis was quantifi ed by histologic scoring.Results: Lupeol signifi cantly inhibited LPS-induced IκBa and p38-MAPK phosphorylation. The productions of proinfl ammatory cytokines in both IEC and macrophages were also inhibited with lupeol pretreatment. The administration of lupeol signifi cantly reduced the severity of colitis, as assessed based on histology in the both murine colitis models. Conclusions: Lupeol may block the p38-MAPK/IκBa phosphorylation, inhibit the activation of IECs and macrophages, and attenuate experimental murine colitis. These fi ndings suggest that lupeol is a potential therapeutic agent for infl ammatory bowel diseases.