title: Celastrol targets IRAKs to block Toll-like receptor 4-mediated nuclear factor-κB activation.
abstract: OBJECTIVE
  Celastrol has been established as a nuclear factor-κB (NF-κB) activation inhibitor; however, the exact mechanism behind this action is still unknown. Using text-mining technology, the authors predicted that interleukin-1 receptor-associated kinases (IRAKs) are potential celastrol targets, and hypothesized that targeting IRAKs might be one way that celastrol inhibits NF-κB. This is because IRAKs are key molecules for some crucial pathways to activate NF-κB (e.g., the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily).
  
  
  METHODS
  The human hepatocellular cell line (HepG2) treated with palmitic acid (PA) was used as a model for stimulating TLR4/NF-κB activation, in order to observe the potential effects of celastrol in IRAK regulation and NF-κB inhibition. The transfection of small interfering RNA was used for down-regulating TLR4, IRAK1 and IRAK4, and the Western blot method was used to detect changes in the protein expressions.
  
  
  RESULTS
  The results showed that celastrol could effectively inhibit PA-caused TLR4-dependent NF-κB activation in the HepG2 cells; PA also activated IRAKs, which were inhibited by celastrol. Knocking down IRAKs abolished PA-caused NF-κB activation.
  
  
  CONCLUSIONS
  The results for the first time show that targeting IRAKs is one way in which celastrol inhibits NF-κB activation.
authors.affiliation: Department of Clinical Laboratory Diagnostics, Postgraduate Education College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China.|Sino-French Cooperative Central Laboratory, Shanghai Gongli Hospital, Second Military Medical University, Shanghai 200135, China.
authors.forename: Yu-fan
authors.initials: YF
authors.lastname: Shen
authors.affiliation: Sino-French Cooperative Central Laboratory, Shanghai Gongli Hospital, Second Military Medical University, Shanghai 200135, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Sino-French Cooperative Central Laboratory, Shanghai Gongli Hospital, Second Military Medical University, Shanghai 200135, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Sino-French Cooperative Central Laboratory, Shanghai Gongli Hospital, Second Military Medical University, Shanghai 200135, China.
authors.forename: Fan-fan
authors.initials: FF
authors.lastname: Cao
authors.affiliation: Sino-French Cooperative Central Laboratory, Shanghai Gongli Hospital, Second Military Medical University, Shanghai 200135, China.|U972, Inserm, Lavoisier Building, Paul Brousse Hospital, 94807, Villejuif Cedex, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Uzan
authors.affiliation: Sino-French Cooperative Central Laboratory, Shanghai Gongli Hospital, Second Military Medical University, Shanghai 200135, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
authors.affiliation: Sino-French Cooperative Central Laboratory, Shanghai Gongli Hospital, Second Military Medical University, Shanghai 200135, China.|U972, Inserm, Lavoisier Building, Paul Brousse Hospital, 94807, Villejuif Cedex, France.
authors.forename: Deng-hai
authors.initials: DH
authors.lastname: Zhang
mesh_terms: D056945:Hep G2 Cells; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D053978:Pentacyclic Triterpenes; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014315:Triterpenes; C507768:IRAK1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C050414:celastrol