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Incensole Acetate, a Novel Anti-Inflammatory Compound Isolated from Boswellia Resin, Inhibits Nuclear Factor-B Activation

Department of Medicinal Chemistry and Natural Products, Medical Faculty (A.M, R.M.) and Department of Pharmacology and Experimental Therapeutics, School of Pharmacy (A.M., E.S.), Hebrew University, Jerusalem, Israel; School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Israel (Y.K.); Departments of Behavioral Sciences and Molecular Biology, the College of Judea and Samaria, Ariel, Israel (E.F.); Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Giessen, Germany (M.L.S., F.R.); University of Freiburg Medical School, Department of Psychiatry, Germany (B.L.F.); Departamento Biologia Celular, Fisiologia e Inmunologia, Facultad de Medicina, Universidad de Cordoba, Spain (E.M.); and the Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel (Y.B.)

Boswellia resin is a major anti-inflammatory agent in herbal medical tradition, as well as a common food supplement. Its anti-inflammatory activity has been attributed to boswellic acid and its derivatives. Here, we re-examined the anti-inflammatory effect of the resin, using inhibitor of nuclear factor-B (IB) degradation in tumor necrosis factor (TNF) -stimulated HeLa cells for a bioassay-guided fractionation. We thus isolated two novel nuclear factor-B (NF-B) inhibitors from the resin, their structures elucidated as incensole acetate (IA) and its nonacetylated form, incensole (IN). IA inhibited TAK/TAB-mediated IB kinase (IKK) activation loop phosphorylation, resulting in the inhibition of cytokine and lipopolysaccharide-mediated NF-B activation. It had no effect on IKK activity in vitro, and it did not suppress IB phosphorylation in costimulated T-cells, indicating that the kinase inhibition is neither direct nor does it affect all NF-B activation pathways. The inhibitory effect seems specific; IA did not interfere with TNF-induced activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. IA treatment had a robust anti-inflammatory effect in a mouse inflamed paw model. Cembrenoid diterpenoids, specifically IA and its derivatives, may thus constitute a potential novel group of NF-B inhibitors, originating from an ancient anti-inflammatory herbal remedy.

Received for publication June 6, 2007.

Accepted for publication September 6, 2007.

Address correspondence to: Arieh Moussaieff, Department of Medicinal Chemistry and Natural Products, Medical Faculty, Hebrew University, Jerusalem 91120, Israel. E-mail: ariehm{at}ekmd.huji.ac.il

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