Abstract
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-κBα (IκBα) degradation in tumor necrosis factor (TNF) α-stimulated HeLa cells for a bioassay-guided fractionation. We thus isolated two novel nuclear factor-κB (NF-κB) inhibitors from the resin, their structures elucidated as incensole acetate (IA) and its nonacetylated form, incensole (IN). IA inhibited TAK/TAB-mediated IκB kinase (IKK) activation loop phosphorylation, resulting in the inhibition of cytokine and lipopolysaccharide-mediated NF-κB activation. It had no effect on IKK activity in vitro, and it did not suppress IκBα phosphorylation in costimulated T-cells, indicating that the kinase inhibition is neither direct nor does it affect all NF-κB activation pathways. The inhibitory effect seems specific; IA did not interfere with TNFα-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-κB inhibitors, originating from an ancient anti-inflammatory herbal remedy.
Footnotes
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This work was supported by a EC 5th framework consortium grant number QLK3-CT-2000-00-463 (Anti-Inflammatory Natural Products consortium), and by the Miriam and Sheldon Adelson program in Neural Repair and Rehabilitation for support (to R.M.).
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.038810.
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ABBREVIATIONS: NF-κB, nuclear factor κB; IκB, inhibitor of nuclear factor-κB; IKK, IκB kinase; TAK, transforming growth factor β-activated kinase; TAB, transforming growth factor β-activated kinase-binding protein; IA, incensole acetate; IN, incensole; PE, petroleum ether; HPLC, high-performance liquid chromatography; GC-MS, gas chromatograph-mass spectrometry; LTR, long-terminal repeat; TNFα, tumor necrosis factor-α; PBS, phosphate-buffered saline; PMA, phorbol 12-myristate 13-acetate; NP-40, Nonidet P-40; WB, Western blotting; GST, glutathione transferase; JNK, C-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; WB, Western blotting.
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↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received June 6, 2007.
- Accepted September 6, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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