TY - JOUR
T1 - Inhibition of NF-κB activation through targeting IκB kinase by celastrol, a quinone methide triterpenoid
AU - Lee, Jeong Hyung
AU - Koo, Tae Hyeon
AU - Yoon, Hyunkyung
AU - Jung, Haeng Sun
AU - Jin, Hui Zi
AU - Lee, Kyeong
AU - Hong, Young Soo
AU - Lee, Jung Joon
PY - 2006/11/15
Y1 - 2006/11/15
N2 - 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.
AB - 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.
KW - Anti-inflammatory and anti-tumor activity
KW - Celastrol
KW - IκB kinase
KW - NF-κB
KW - Quinone methide triterpenoid
UR - http://www.scopus.com/inward/record.url?scp=33750008443&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2006.08.014
DO - 10.1016/j.bcp.2006.08.014
M3 - Article
C2 - 16984800
AN - SCOPUS:33750008443
SN - 0006-2952
VL - 72
SP - 1311
EP - 1321
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 10
ER -