title: Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense.
abstract: OBJECTIVE
  Frankincense, the gum resin derived from Boswellia species, showed anti-inflammatory efficacy in animal models and in pilot clinical studies. Boswellic acids (BAs) are assumed to be responsible for these effects but their anti-inflammatory efficacy in vivo and their molecular modes of action are incompletely understood.
  
  
  METHODS
  A protein fishing approach using immobilized BA and surface plasmon resonance (SPR) spectroscopy were used to reveal microsomal prostaglandin E(2) synthase-1 (mPGES1) as a BA-interacting protein. Cell-free and cell-based assays were applied to confirm the functional interference of BAs with mPGES1. Carrageenan-induced mouse paw oedema and rat pleurisy models were utilized to demonstrate the efficacy of defined BAs in vivo.
  
  
  RESULTS
  Human mPGES1 from A549 cells or in vitro-translated human enzyme selectively bound to BA affinity matrices and SPR spectroscopy confirmed these interactions. BAs reversibly suppressed the transformation of prostaglandin (PG)H(2) to PGE(2) mediated by mPGES1 (IC(50) = 3-10 µM). Also, in intact A549 cells, BAs selectively inhibited PGE(2) generation and, in human whole blood, β-BA reduced lipopolysaccharide-induced PGE(2) biosynthesis without affecting formation of the COX-derived metabolites 6-keto PGF(1α) and thromboxane B(2) . Intraperitoneal or oral administration of β-BA (1 mg·kg(-1) ) suppressed rat pleurisy, accompanied by impaired levels of PGE(2) and β-BA (1 mg·kg(-1) , given i.p.) also reduced mouse paw oedema, both induced by carrageenan.
  
  
  CONCLUSIONS
  Suppression of PGE(2) formation by BAs via interference with mPGES1 contribute to the anti-inflammatory effectiveness of BAs and of frankincense, and may constitute a biochemical basis for their anti-inflammatory properties.
authors.affiliation: Pharmaceutical Institute, University of Tuebingen, Tuebingen, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Siemoneit
authors.forename: A
authors.initials: A
authors.lastname: Koeberle
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: F
authors.initials: F
authors.lastname: Dehm
authors.forename: M
authors.initials: M
authors.lastname: Verhoff
authors.forename: S
authors.initials: S
authors.lastname: Reckel
authors.forename: T J
authors.initials: TJ
authors.lastname: Maier
authors.forename: J
authors.initials: J
authors.lastname: Jauch
authors.forename: H
authors.initials: H
authors.lastname: Northoff
authors.forename: F
authors.initials: F
authors.lastname: Bernhard
authors.forename: V
authors.initials: V
authors.lastname: Doetsch
authors.forename: L
authors.initials: L
authors.lastname: Sautebin
authors.forename: O
authors.initials: O
authors.lastname: Werz
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D029743:Boswellia / Q000737:chemistry*; D002384:Catalysis; D002460:Cell Line; D002474:Cell-Free System; D006801:Humans; D007124:Immunoenzyme Techniques; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D000071876:Prostaglandin-E Synthases; D051381:Rats; D017208:Rats, Wistar; D020349:Surface Plasmon Resonance; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D014315:Triterpenes; C054625:boswellic acid; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases