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Journal of Integrative Medicine ›› 2016, Vol. 14 ›› Issue (3): 203-208.doi: 10.1016/S2095-4964(16)60257-1

• Research Article • Previous Articles     Next Articles

Celastrol targets IRAKs to block Toll-like receptor 4-mediated nuclear factor-κB activation

Yu-fanShena,b, XueZhangb, YingWangb, Fan-fanCaob, GeorgesUzanb,c, BinPengd , Deng-haiZhangb,c   

  1. a Department of Clinical Laboratory Diagnostics, Postgraduate Education College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
    b Sino-French Cooperative Central Laboratory, Shanghai Gongli Hospital, Second Military Medical University, Shanghai 200135, China
    c U972, Inserm, Lavoisier Building, Paul Brousse Hospital, 94807, Villejuif Cedex, France
  • Received:2016-01-07 Accepted:2016-03-08 Online:2016-05-15 Published:2016-05-15
  • Contact: Bin Peng; E-mail: Deng-hai Zhang, Professor, PhD, MD; E-mail:


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).


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.


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.


The results for the first time show that targeting IRAKs is one way in which celastrol inhibits NF-κB activation.

Key words: Celastrol, Interleukin-1 receptor-associated kinases, Nuclear factor-kappa B, Toll-like receptor 4, Hepatocytes

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