title: 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.
authors.affiliation: Anticancer Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, 52 Aueun-Dong, Yuseong-Gu, Daejeon, Republic of Korea.
authors.forename: Jeong-Hyung
authors.initials: JH
authors.lastname: Lee
authors.forename: Tae Hyeon
authors.initials: TH
authors.lastname: Koo
authors.forename: Hyunkyung
authors.initials: H
authors.lastname: Yoon
authors.forename: Haeng Sun
authors.initials: HS
authors.lastname: Jung
authors.forename: Hui Zi
authors.initials: HZ
authors.lastname: Jin
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.forename: Young-Soo
authors.initials: YS
authors.lastname: Hong
authors.forename: Jung Joon
authors.initials: JJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D051550:I-kappa B Kinase; C050414:celastrol