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

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dc.contributor.authorJ H Lee-
dc.contributor.authorT H Koo-
dc.contributor.authorH Yoon-
dc.contributor.authorHaeng Sun Jung-
dc.contributor.authorH Z Jin-
dc.contributor.authorKyeong Lee-
dc.contributor.authorYoung-Soo Hong-
dc.contributor.authorJung Joon Lee-
dc.date.accessioned2017-04-19T09:05:22Z-
dc.date.available2017-04-19T09:05:22Z-
dc.date.issued2006-
dc.identifier.issn0006-2952-
dc.identifier.uri10.1016/j.bcp.2006.08.014ko
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/7615-
dc.description.abstractCelastrol, 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.-
dc.publisherElsevier-
dc.titleInhibition of NF-κB activation through targeting IκB kinase by celastrol, a quinone methide triterpenoid-
dc.title.alternativeInhibition of NF-κB activation through targeting IκB kinase by celastrol, a quinone methide triterpenoid-
dc.typeArticle-
dc.citation.titleBiochemical Pharmacology-
dc.citation.number10-
dc.citation.endPage1321-
dc.citation.startPage1311-
dc.citation.volume72-
dc.contributor.affiliatedAuthorHaeng Sun Jung-
dc.contributor.affiliatedAuthorKyeong Lee-
dc.contributor.affiliatedAuthorYoung-Soo Hong-
dc.contributor.affiliatedAuthorJung Joon Lee-
dc.contributor.alternativeName이정형-
dc.contributor.alternativeName구태현-
dc.contributor.alternativeName윤현경-
dc.contributor.alternativeName정행선-
dc.contributor.alternativeNameJin-
dc.contributor.alternativeName이경-
dc.contributor.alternativeName홍영수-
dc.contributor.alternativeName이정준-
dc.identifier.bibliographicCitationBiochemical Pharmacology, vol. 72, no. 10, pp. 1311-1321-
dc.identifier.doi10.1016/j.bcp.2006.08.014-
dc.subject.keywordanti-inflammatory and anti-tumor activity-
dc.subject.keywordcelastrol-
dc.subject.keywordIκB kinase-
dc.subject.keywordNF-κB-
dc.subject.keywordquinone methide triterpenoid-
dc.subject.localanti-inflammatory and anti-tumor activity-
dc.subject.localCelastrol-
dc.subject.localcelastrol-
dc.subject.localIκB kinase-
dc.subject.localNuclear factor-kappa B-
dc.subject.localnuclear factor κB-
dc.subject.localNf-κb-
dc.subject.localNF-kB-
dc.subject.localnuclear factor kappa B-
dc.subject.localNF-κB (nuclear factor kappa-B)-
dc.subject.localNF-kappaB-
dc.subject.localNuclear factor-κb-
dc.subject.localNF-κ B-
dc.subject.localNF-κB-
dc.subject.localNF-kappa B-
dc.subject.localNuclear factor κB (NF-κB)-
dc.subject.localNuclear factor κB-
dc.subject.localNFκB-
dc.subject.localNf-κB-
dc.subject.localNuclear factor-κB-
dc.subject.localnuclear factorκB-
dc.subject.localNuclear factor (NF)-κB-
dc.subject.localNuclear factor kappa B-
dc.subject.localnuclear factor-κB-
dc.subject.localNF-ΚB-
dc.subject.localNuclear factor-kappa B (NF-κB)-
dc.subject.localNuclear factor-kappaB-
dc.subject.localnuclear factor-kappaB-
dc.subject.localnuclear factor-kappaB (NF-κB)-
dc.subject.localNFkappaB-
dc.subject.localNuclear factor kappaB-
dc.subject.localquinone methide triterpenoid-
dc.description.journalClassY-
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Ochang Branch Institute > Chemical Biology Research Center > 1. Journal Articles
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