Inhibition of NF-kappaB activation through targeting IkappaB kinase by celastrol, a quinone methide triterpenoid.
Celastrol, a quinone methide triterpenoid, was isolated as an inhibitor of NF-kappaB from Celastrus orbiculatus. This compound dose-dependently inhibited a variety of stimuli-induced NF-kappaB-regulated gene expression and the DNA-binding of NF-kappaB in different cell lines without affecting DNA-binding activity of AP-1. Preincubation of celastrol completely blocked the LPS-, TNF-alpha-, or PMA-induced degradation and phosphorylation of IkappaBalpha. Importantly, celastrol inhibited IKK activity and the constitutively active IKKbeta activity in a dose-dependent manner without either affecting the NF-kappaB activation induced by RelA over-expression or directly suppressing the DNA-binding of activated NF-kappaB. However, mutation of cysteine 179 in the activation loop of IKKbeta abolished sensitivity towards to celastrol, suggesting that celastrol suppressed the NF-kappaB activation by targeting cysteine 179 in the IKK. To verify that celastrol is a NF-kappaB inhibitor, we investigated its effect on some NF-kappaB target genes expressions. Celastrol prevented not only LPS- induced mRNA expression of iNOS and TNF-alpha, but also TNF-alpha-induced Bfl-1/A1 expression, a prosurvival Bcl-2 homologue. Consistent with these results, celastrol significantly suppressed the production of NO and TNF-alpha in LPS-stimulated RAW264.7 cells, and increased the cytotoxicity of TNF-alpha in HT-1080 cells. We also demonstrated that celastrol showed anti-inflammatory and anti-tumor activities in animal models. Taken together, this study extends our understanding on the molecular mechanisms underlying the anti-inflammatory and anti-cancer activities of celastrol and celastrol-containing medicinal plant, which would be a valuable candidate for the intervention of NF-kappaB-dependent pathological conditions.[1]References
- Inhibition of NF-kappaB activation through targeting IkappaB kinase by celastrol, a quinone methide triterpenoid. Lee, J.H., Koo, T.H., Yoon, H., Jung, H.S., Jin, H.Z., Lee, K., Hong, Y.S., Lee, J.J. Biochem. Pharmacol. (2006) [Pubmed]
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