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Title 

Inhibition of NF-κB activation through targeting IκB kinase by celastrol, a quinone methide triterpenoid

Authors 

J H LeeT H KooH YoonHaeng Sun JungH Z JinKyeong LeeYoung-Soo HongJung Joon Lee

Publisher 

Elsevier

Issue Date 

2006

Citation 

Biochemical Pharmacology, vol. 72, no. 10, pp. 1311-1321

Keywords 

anti-inflammatory and anti-tumor activitycelastrolIκB kinaseNF-κBquinone methide triterpenoid

Abstract 

Celastrol, a quinone methide triterpenoid, was isolated as an inhibitor of NF-κB from Celastrus orbiculatus. This compound dose-dependently inhibited a variety of stimuli-induced NF-κB-regulated gene expression and the DNA-binding of NF-κB in different cell lines without affecting DNA-binding activity of AP-1. Preincubation of celastrol completely blocked the LPS-, TNF-α-, or PMA-induced degradation and phosphorylation of IκBα. Importantly, celastrol inhibited IKK activity and the constitutively active IKKβ activity in a dose-dependent manner without either affecting the NF-κB activation induced by RelA over-expression or directly suppressing the DNA-binding of activated NF-κB. However, mutation of cysteine 179 in the activation loop of IKKβ abolished sensitivity towards to celastrol, suggesting that celastrol suppressed the NF-κB activation by targeting cysteine 179 in the IKK. To verify that celastrol is a NF-κB inhibitor, we investigated its effect on some NF-κB target genes expressions. Celastrol prevented not only LPS-induced mRNA expression of iNOS and TNF-α, but also TNF-α-induced Bfl-1/A1 expression, a prosurvival Bcl-2 homologue. Consistent with these results, celastrol significantly suppressed the production of NO and TNF-α in LPS-stimulated RAW264.7 cells, and increased the cytotoxicity of TNF-α 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-κB-dependent pathological conditions.

ISSN 

0006-2952

Link 

http://dx.doi.org/10.1016/j.bcp.2006.08.014

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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