title: Inhibitory effects of teuclatriol, a sesquiterpene from salvia mirzayanii, on nuclear factor-κB activation and expression of inflammatory mediators.
abstract: BACKGROUND
  Salvia mirzayanii Rech. f. & Esfand. is an endemic plant, which is only distributed in the south of Iran. In traditional Iranian medicine, the aerial parts of Salvia mirzayanii have been used for infections, inflammatory diseases, and as a tonic. From this plant, the sesquiterpene teuclatriol was isolated by bioactivity-guided fractionation due to its anti-proliferative actions on human lymphocytes. The guaiane sesquiterpene is lacking the methylene-γ-lactone function that is typically involved in the inhibiting properties of sesquiterpenes on NF-κB, a pivotal transcription factor in inflammatory processes. We here investigated anti-inflammatory effects of teuclatriol on human macrophage-like and endothelial cells.
  
  
  METHODS
  Non-toxic doses of teuclatriol were determined for both cell types by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-assay. The effect of teuclatriol on the activity of NF-κB in LPS-stimulated human monocytic THP-1 cells was studied using infrared electrophoretic mobility shift assay (IR-EMSA) using curcumin as positive control (32µM). THP-1 were differentiated into macrophage-like cells and evaluated for TNF-α secretion by L929 bioassay following stimulation with LPS and treatment with teuclatriol. Inflammatory gene expression in human umbilical vein endothelial cells (HUVEC), modeling target cells for TNF-α-induced inflammatory gene activation, was investigated by real-time RT-PCR.
  
  
  RESULTS
  The LPS-induced DNA binding activity of NF-κB in THP-1 was significantly decreased by non-toxic doses of teuclatriol (312 and 390µM). Teuclatriol reduced the production of TNF-α in a dose-dependent manner. mRNA levels of both monocyte chemoattractant protein (MCP)-1 and toll-like receptor (TLR)2 were decreased in TNF-α-activated HUVEC.
  
  
  CONCLUSIONS
  These data show an inhibitory effect of teuclatriol on NF-κB signaling at doses of 312µM and higher, validating the traditional use of Salvia mirzayanii in the treatment of inflammatory diseases. Future work on the mode of action of teuclatriol may provide new lead structures with NF-κB inhibiting properties, lacking possible side effects mediated via alkylating centers of sesquiterpene lactones.
authors.affiliation: Department of Immunology, Dr. Sheikh Educational, Research and Treatment Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Akram
authors.initials: A
authors.lastname: Ziaei
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hoppstädter
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Kiemer
authors.affiliation: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ramezani
authors.affiliation: Immunology Department, Autoimmune Disease Research Center, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: amirghz@sums.ac.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Amirghofran
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Diesel
mesh_terms: D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis; D003474:Curcumin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D027544:Salvia / Q000737:chemistry*; D012717:Sesquiterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D045789:Sesquiterpenes, Guaiane / Q000302:isolation & purification / Q000494:pharmacology*; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; C000595588:teuclatriol; D003474:Curcumin
keywords: Endothelial cell; MCP-1; Macrophage; Salvia mirzayanii; TLR2; TNF-α