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Inhibition of NF-kappa B activation through targeting I kappa B kinase by celastrol, a quinone methide triterpenoid.

Abstract：

: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-kappa B-regulated gene expression and the DNA-binding of NF-kappa B 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 I kappa B alpha. Importantly, celastrol inhibited IKK activity and the constitutively active IKK beta activity in a dose-dependent manner without either affecting the NF-kappa B activation induced by RelA over-expression or directly suppressing the DNA-binding of activated NF-kappa B. However, mutation of cysteine 179 in the activation loop of IKK beta abolished sensitivity towards to celastrol, suggesting that celastrol suppressed the NF-kappa B activation by targeting cysteine 179 in the IKK. To verify that celastrol is a NF-kappa B inhibitor, we investigated its effect on some NF-kappa B 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-kappa B-dependent pathological conditions.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Lee JH,Koo TH,Yoon H,Jung HS,Jin HZ,Lee K,Hong YS,Lee JJ

doi

10.1016/j.bcp.2006.08.014

subject

Has Abstract

pub_date

2006-11-15 00:00:00

pages

1311-21

issue

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(06)00504-1

journal_volume

pub_type

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Inhibition of NF-kappa B activation through targeting I kappa B kinase by celastrol, a quinone methide triterpenoid.