title: Potent anti-inflammatory activity of ursolic acid, a triterpenoid antioxidant, is mediated through suppression of NF-κB, AP-1 and NF-AT.
abstract: BACKGROUND
  Ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, is the major component of many plants including apples, basil, cranberries, peppermint, rosemary, oregano and prunes and has been reported to possess antioxidant and anti-tumor properties. These properties of UA have been attributed to its ability to suppress NF-κB (nuclear factor kappa B) activation. Since NF-κB, in co-ordination with NF-AT (nuclear factor of activated T cells) and AP-1(activator protein-1), is known to regulate inflammatory genes, we hypothesized that UA might exhibit potent anti-inflammatory effects.
  
  
  RESULTS
  The anti-inflammatory effects of UA were assessed in activated T cells, B cells and macrophages. Effects of UA on ERK, JNK, NF-κB, AP-1 and NF-AT were studied to elucidate its mechanism of action. In vivo efficacy of UA was studied using mouse model of graft-versus-host disease. UA inhibited activation, proliferation and cytokine secretion in T cells, B cells and macrophages. UA inhibited mitogen-induced up-regulation of activation markers and co-stimulatory molecules in T and B cells. It inhibited mitogen-induced phosphorylation of ERK and JNK and suppressed the activation of immunoregulatory transcription factors NF-κB, NF-AT and AP-1 in lymphocytes. Treatment of cells with UA prior to allogenic transplantation significantly delayed induction of acute graft-versus-host disease in mice and also significantly reduced the serum levels of pro-inflammatory cytokines IL-6 and IFN-γ. UA treatment inhibited T cell activation even when added post-mitogenic stimulation demonstrating its therapeutic utility as an anti-inflammatory agent.
  
  
  CONCLUSIONS
  The present study describes the detailed mechanism of anti-inflammatory activity of UA. Further, UA may find application in the treatment of inflammatory disorders.
authors.affiliation: Radiation Biology and Health Sciences Division, Bio-Medical Group, Bhabha Atomic Research Centre, Mumbai, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Checker
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Sandur
authors.forename: Deepak
authors.initials: D
authors.lastname: Sharma
authors.forename: Raghavendra S
authors.initials: RS
authors.lastname: Patwardhan
authors.forename: S
authors.initials: S
authors.lastname: Jayakumar
authors.forename: Vineet
authors.initials: V
authors.lastname: Kohli
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
authors.forename: Krishna B
authors.initials: KB
authors.lastname: Sainis
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000097245:Ursolic Acid
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D000975:Antioxidants; D018106:CD28 Antigens; D017252:CD3 Complex; D003208:Concanavalin A; D016207:Cytokines; D020928:Mitogen-Activated Protein Kinases; D008934:Mitogens; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014315:Triterpenes; D000097245:Ursolic Acid