Inhibition of microsomal prostaglandin E2 synthase‐1 as a molecular basis for the anti‐inflammatory actions of boswellic acids from frankincense

• Published in: British journal of pharmacology Vol. 162; no. 1; pp. 147 - 162
• Main Authors: Siemoneit, U, Koeberle, A, Rossi, A, Dehm, F, Verhoff, M, Reckel, S, Maier, TJ, Jauch, J, Northoff, H, Bernhard, F, Doetsch, V, Sautebin, L, Werz, O
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2011; Nature Publishing Group
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; arachidonic acid; Biological and medical sciences; Boswellia - chemistry; boswellic acid; Catalysis; Cell Line; Cell-Free System; Humans; Immunoenzyme Techniques; inflammation; Intramolecular Oxidoreductases - antagonists & inhibitors; Intramolecular Oxidoreductases - metabolism; Male; Medical sciences; Mice; microsomal prostaglandin E2 synthase; Pharmacology. Drug treatments; prostaglandin; Prostaglandin-E Synthases; Rats; Rats, Wistar; Research Papers; Surface Plasmon Resonance; Triterpenes - isolation & purification; Triterpenes - pharmacology; Prostaglandin-endoperoxide synthase; Enzyme; prostaglandin; Arachidonic acid derivatives; Antiinflammatory agent; Prostaglandin E2; Inflammation; Arachidonic acid; Microsome; Eicosanoid; boswellic acid; synthase; Oxidoreductases; microsomal prostaglandin E
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2010.01020.x

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH A protein fishing approach using immobilized BA and surface plasmon resonance (SPR) spectroscopy were used to reveal microsomal prostaglandin E2 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. KEY 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)H2 to PGE2 mediated by mPGES1 (IC50 = 3–10 µM). Also, in intact A549 cells, BAs selectively inhibited PGE2 generation and, in human whole blood, β‐BA reduced lipopolysaccharide‐induced PGE2 biosynthesis without affecting formation of the COX‐derived metabolites 6‐keto PGF1α and thromboxane B2. Intraperitoneal or oral administration of β‐BA (1 mg·kg−1) suppressed rat pleurisy, accompanied by impaired levels of PGE2 and β‐BA (1 mg·kg−1, given i.p.) also reduced mouse paw oedema, both induced by carrageenan. CONCLUSIONS AND IMPLICATIONS Suppression of PGE2 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.