Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense.
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.
Siemoneit
U
U
Pharmaceutical Institute, University of Tuebingen, Tuebingen, Germany.
Koeberle
A
A
Rossi
A
A
Dehm
F
F
Verhoff
M
M
Reckel
S
S
Maier
T J
TJ
Jauch
J
J
Northoff
H
H
Bernhard
F
F
Doetsch
V
V
Sautebin
L
L
Werz
O
O
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*
D000893:Anti-Inflammatory Agents; D014315:Triterpenes; C054625:boswellic acid; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases