title: Ursolic acid inhibits nuclear factor-κB signaling in intestinal epithelial cells and macrophages, and attenuates experimental colitis in mice.
abstract: OBJECTIVE
  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.
  
  
  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-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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jaeyoung
authors.initials: J
authors.lastname: Chun
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Changhyun
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Hwang
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jong Pil
authors.initials: JP
authors.lastname: Im
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: jooskim@snu.ac.kr.
authors.forename: Joo Sung
authors.initials: JS
authors.lastname: Kim
mesh_terms: D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D016207:Cytokines; D016264:Dextran Sulfate; D020672:I-kappa B Proteins; D016753:Interleukin-10; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D014315:Triterpenes; D000097245:Ursolic Acid; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse
keywords: Inflammatory bowel disease; Murine colitis; NFκB; Ursolic acid