title: Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation.
abstract: OBJECTIVE
  Ursolic acid (UA) is a pentacyclic triterpenoid found in most plant species, which has been shown anti-inflammatory and anti-oxidative activities. In this study, we examined the effects of UA on collagen-induced arthritis (CIA) in mice, and to identify the mechanisms underlying the effects.
  
  
  METHODS
  CIA was induced in mice. Two weeks later, the mice were treated with UA (150 mg/kg, ip, 3 times per week) for 4 weeks. The expression of cytokines and oxidative stress markers in joint tissues was measured with immunohistochemistry. The numbers of CD4+IL-17+, CD4+CD25+Foxp3+ and pSTAT3 cells in spleens were determined using confocal immunostaining or flowcytometric analyses. Serum antibody levels and B cell-associated marker mRNAs were analyzed with ELISAs and qRT-PCR, respectively. CD4+ T cells and CD19+ B cells were purified from mice spleens for in vitro studies.
  
  
  RESULTS
  UA treatment significantly reduced the incidence and severity of CIA-induced arthritis, accompanied by decreased expression of proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-21 and IL-17) and oxidative stress markers (nitrotyrosine and iNOS) in arthritic joints. In CIA mice, UA treatment significantly decreased the number of Th17 cells, while increased the number of Treg cells in the spleens, which was consistent with decreased expression of pSTAT3, along with IL-17 and RORγt in the splenocytes. In addition, UA treatment significantly reduced the serum CII-specific IgG levels in CIA mice. The inhibitory effects of UA on Th17 cells were confirmed in an in vitro model of Th17 differentiation. Furthermore, UA dose-dependently suppressed the expression of B cell-associated markers Bcl-6, Blimp1 and AID mRNAs in purified CD19+ B cells pretreated with IL-21 or LPS in vitro.
  
  
  CONCLUSIONS
  UA treatment significantly ameliorates CIA in mice via suppression of Th17 and differentiation. By targeting pathogenic Th17 cells and autoantibody production, UA may be useful for the treatment of autoimmune arthritis and other Th17-related diseases.
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Seung-ye
authors.initials: SY
authors.lastname: Baek
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Jaeseon
authors.initials: J
authors.lastname: Lee
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Dong-gun
authors.initials: DG
authors.lastname: Lee
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Mi-kyung
authors.initials: MK
authors.lastname: Park
authors.affiliation: 1] The Rheumatism Research Center, Catholic Research Institute of Medical Science, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea [2] Divison of Rheumatology, Department of Internal Medicine, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul 137-040, South Korea.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.affiliation: 1] The Rheumatism Research Center, Catholic Research Institute of Medical Science, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea [2] Divison of Rheumatology, Department of Internal Medicine, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul 137-040, South Korea.
authors.forename: Seung-ki
authors.initials: SK
authors.lastname: Kwok
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Mi-la
authors.initials: ML
authors.lastname: Cho
authors.affiliation: 1] The Rheumatism Research Center, Catholic Research Institute of Medical Science, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea [2] Divison of Rheumatology, Department of Internal Medicine, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul 137-040, South Korea.
authors.forename: Sung-hwan
authors.initials: SH
authors.lastname: Park
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D058504:Th17 Cells / Q000276:immunology*; D014315:Triterpenes / Q000276:immunology*; D000097245:Ursolic Acid
chemical_list: D014315:Triterpenes; D000097245:Ursolic Acid
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