Incensole acetate, a novel anti-inflammatory compound isolated from Boswellia resin, inhibits nuclear factor-kappa B activation.
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-kappaB alpha (IkappaB alpha) degradation in tumor necrosis factor (TNF) alpha-stimulated HeLa cells for a bioassay-guided fractionation. We thus isolated two novel nuclear factor-kappaB (NF-kappaB) inhibitors from the resin, their structures elucidated as incensole acetate (IA) and its nonacetylated form, incensole (IN). IA inhibited TAK/TAB-mediated IkappaB kinase (IKK) activation loop phosphorylation, resulting in the inhibition of cytokine and lipopolysaccharide-mediated NF-kappaB activation. It had no effect on IKK activity in vitro, and it did not suppress IkappaB alpha phosphorylation in costimulated T-cells, indicating that the kinase inhibition is neither direct nor does it affect all NF-kappaB activation pathways. The inhibitory effect seems specific; IA did not interfere with TNFalpha-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-kappaB inhibitors, originating from an ancient anti-inflammatory herbal remedy.
Moussaieff
Arieh
A
Department of Medicinal Chemistry and Natural Products, Medical Faculty, Hebrew University, Jerusalem 91120, Israel. ariehm@ekmd.huji.ac.il
Shohami
Esther
E
Kashman
Yoel
Y
Fride
Ester
E
Schmitz
M Lienhard
ML
Renner
Florian
F
Fiebich
Bernd L
BL
Munoz
Eduardo
E
Ben-Neriah
Yinon
Y
Mechoulam
Raphael
R
D000085:Acetates / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D029743:Boswellia / Q000737:chemistry; D005260:Female; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000085:Acetates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B