title: Citrus peel polymethoxyflavones nobiletin and tangeretin suppress LPS- and IgE-mediated activation of human intestinal mast cells.
abstract: OBJECTIVE
  Allergic diseases with mast cells (MC) as main effector cells show an increased prevalence. MC also play an essential role in other inflammatory conditions. Therapeutical use of anti-inflammatory nutraceuticals directly targeting MC activation could be of interest for afflicted patients. Nobiletin and tangeretin are citrus peel polymethoxyflavones, a group of citrus flavonoids, possessing anticancer, antimetastatic, and anti-inflammatory activities. Here, we analyzed the effects of nobiletin/tangeretin on LPS- and IgE-mediated stimulation of human intestinal mast cells (hiMC).
  
  
  METHODS
  MC isolated from human intestinal tissue were treated with different concentrations of nobiletin or tangeretin prior to stimulation via LPS/sCD14 or IgE-dependently. Degranulation, pro-inflammatory cytokine expression and phosphorylation of ERK1/2 were examined.
  
  
  RESULTS
  Expression of CXCL8, CCL3, CCL4 and IL-1β in response to LPS-mediated stimulation was inhibited by nobiletin/tangeretin. hiMC activated IgE-dependently showed a reduced release of β-hexosaminidase and cysteinyl LTC4in response to nobiletin, but not in response to tangeretin. Expression of CXCL8, CCL2, CCL3, CCL4 and TNF in IgE-dependently activated hiMC was decreased in a dose-dependent manner following treatment with nobiletin/tangeretin. IL-1β expression was only reduced by tangeretin. Compared to treatment with NF-κB inhibitor BMS345541 or MEK-inhibitor PD98059, nobiletin and tangeretin showed similar effects on mediator production. Phosphorylation of ERK1/2 upon IgE-mediated antigen stimulation was significantly suppressed by nobiletin and tangeretin.
  
  
  CONCLUSIONS
  Nobiletin and, to a lesser extent, tangeretin could be considered as anti-inflammatory nutraceuticals by reducing release and production of proinflammatory mediators in MC.
authors.affiliation: Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70593, Stuttgart, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hagenlocher
authors.affiliation: Clinic for Visceral Surgery, Katharinenhospital, Kriegsbergstraße 60, 70174, Stuttgart, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Feilhauer
authors.affiliation: Department of General, Visceral, and Thorax Surgery, Marienhospital, Böheimstraße 37, 70199, Stuttgart, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schäffer
authors.affiliation: Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70593, Stuttgart, Germany.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Bischoff
authors.affiliation: Department of Nutritional Medicine, University of Hohenheim, Fruwirthstraße 12, 70593, Stuttgart, Germany. Lorentz@uni-hohenheim.de.
authors.forename: Axel
authors.initials: A
authors.lastname: Lorentz
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002957:Citrus / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism; D047309:Flavones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007073:Immunoglobulin E; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000187:drug effects; D008070:Lipopolysaccharides; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology*; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D047309:Flavones; D005419:Flavonoids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010936:Plant Extracts; D007073:Immunoglobulin E; C008661:nobiletin; D020928:Mitogen-Activated Protein Kinases; D001619:beta-N-Acetylhexosaminidases; C059006:tangeretin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Allergy; Citrus fruits; Flavonoids; Mast cells; Nutraceuticals