title: Neomangiferin modulates the Th17/Treg balance and ameliorates colitis in mice.
abstract: BACKGROUND
  Anemarrhena asphodeloides (Liliaceae family) and Mangifera indica L. (Anacardiaceae family) contain neomangiferin as the main active constituent and have been used to treat inflammation, asthma, and pain.
  
  
  OBJECTIVE
  A preliminary study found that neomangiferin inhibited splenic T cell differentiation into Th17 cells and promoted Treg cell production in vitro. Therefore, we examined its anti-colitic effects in vitro and in vivo.
  
  
  METHODS
  Splenocytes isolated from C57BL/6J mice were treated with neomangiferin. Colitis was either induced in vivo by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) to C57BL/6J mice or occurred spontaneously in colitis caused by interleukin (IL)-10 knockout at age of 13 weeks. Mice were treated daily with neomangiferin or sulfasalazine. Inflammatory markers, cytokines, enzymes and transcription factors were measured by enzyme-linked immunosorbent assay, immunoblot, and flow cytometry.
  
  
  RESULTS
  Neomangiferin suppressed retinoic acid receptor-related orphan receptor gamma t (RORγt) and IL-17 expression in IL-6/transforming growth factor β-stimulated Th17 splenocytes and increased IL-10 expression in vitro. Mouse TNBS-induced colon shortening, macroscopic score, and myeloperoxidase activity were inhibited by neomangiferin, which also reduced TNBS-induced activation of nuclear factor-κB and extracellular signal-regulated kinases, as well as expression of inducible nitric oxide synthase and cyclooxygenase-2. In addition, neomangiferin inhibited TNBS-induced expression of tumor necrosis factor-α, IL-17, IL-6, and IL-1β, and increased IL-10 expression. Neomangiferin inhibited TNBS-induced differentiation to Th17 cells and promoted the development of Treg cells. Moreover, in IL-10(-/-) mice, neomangiferin inhibited colonic myeloperoxidase activity, suppressed Th17 cell differentiation, and reduced levels of TNF-α and IL-17.
  
  
  CONCLUSIONS
  Neomangiferin may restore the balance between Th17/Treg cells by suppressing IL-17 and RORγt expression and inducing IL-10 and forkhead box P3 expression, thus ameliorating colitis.
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, South Korea.
authors.forename: Su-Min
authors.initials: SM
authors.lastname: Lim
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, South Korea.
authors.forename: Geum-Dan
authors.initials: GD
authors.lastname: Kang
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, South Korea.
authors.forename: Jin-Ju
authors.initials: JJ
authors.lastname: Jeong
authors.affiliation: DongWha Pharm Research Institute, 35-71, Topsil-ro, Giheung-gu, Yongin-Shi, Gyeonggi, 46-902 South Korea.
authors.forename: Hyun Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, South Korea. Electronic address: dhkim@khu.ac.kr.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects / Q000201:enzymology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D058504:Th17 Cells / Q000187:drug effects*; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D005960:Glucosides; D020381:Interleukin-17; D015850:Interleukin-6; D016328:NF-kappa B; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; C442164:neomangiferin; D016753:Interleukin-10; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Colitis; Differentiation; IL-10 knockout; Neomangiferin; Th17; Treg