title: The guggulsterone derivative GG-52 inhibits NF-κB signaling in bone marrow-derived dendritic cells and attenuates colitis in IL-10 knockout mice.
abstract: OBJECTIVE
  We previously demonstrated that the novel guggulsterone derivative guggulsterone-52 (GG-52) inhibited the activation of nuclear factor (NF)-κB signaling in intestinal epithelial cells and had preventive and therapeutic effects on dextran sulfate sodium-induced acute colitis. This study investigates the anti-inflammatory effects of GG-52 on bone marrow-derived dendritic cells (BMDCs) and chronic colitis in IL-10(-/-) mice.
  
  
  METHODS
  BMDCs were generated from the femurs of C57BL/6 wild-type and IL-10(-/-) mice. BMDCs were stimulated with lipopolysaccharide (LPS) in the presence or absence of GG-52. The effect of GG-52 on NF-κB signaling in BMDCs was examined by real-time RT-PCR for IL-12p40 and TNF-α gene expression, western blotting for IκBα degradation, and electrophoretic mobility shift assay. For in vivo studies, wild-type or IL-10(-/-) mice were treated with or without GG-52. Colitis was quantified by the evaluation of histopathological findings. Double immunofluorescence staining for CD11c and phosphorylated IκB kinase (IKK)-α was performed to detect IKK activation in DCs in colonic tissue.
  
  
  RESULTS
  GG-52 significantly inhibited LPS-induced IL-12p40 and TNF-α gene expression, IκBα degradation, and NF-κB DNA binding activity in BMDCs. In the IL-10(-/-) mouse model chronic colitis, administration of GG-52 significantly reduced the severity of colitis as assessed by histopathology, and suppressed IKK activation in DCs in colonic tissue.
  
  
  CONCLUSIONS
  These results indicate that the novel guggulsterone derivative GG-52 blocks NF-κB activation in BMDCs and ameliorates chronic colitis in IL-10(-/-) mice, which suggest that GG-52 is a potential therapeutic agent for inflammatory bowel diseases.
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Seung Joo
authors.initials: SJ
authors.lastname: Kang
authors.forename: Jung Mogg
authors.initials: JM
authors.lastname: Kim
authors.forename: Seong-Joon
authors.initials: SJ
authors.lastname: Koh
authors.forename: Su Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Jong Pil
authors.initials: JP
authors.lastname: Im
authors.forename: Hyun Chae
authors.initials: HC
authors.lastname: Jung
authors.forename: Joo Sung
authors.initials: JS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D015870:Gene Expression; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011283:Pregnenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C550854:GG-52 compound; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011283:Pregnenes; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D051550:I-kappa B Kinase