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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 int erleukin-1 receptor-associated kinases(IRA Ks) 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 inter leukin-1 receptor(IL-1R)/Toll- like receptor(TLR) superfamily).METHODS: The human hepatocellular cell line(Hep G2) 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 Hep G 2 cells; PA also activated IRAKs, which were inhibited by celastrol. Knocking down IRAKs abolished PA-caused NF-κB activation.CONCLUSION: The results for the first time show that targeting IRAKs is one way in which celastrol inhibits NF-κB activation.
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 int erleukin-1 receptor-associated kinases (IRA Ks) 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 (eg, the inter leukin-1 receptor (HP-1R) / Toll-like receptor (TLR) superfamily. METHODS: The human hepatocellular cell line (Hep G2) treated with palmitic acid (PA) was used as a model for stimulating TLR4 / NF- 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 th at celastrol could effectively inhibit PA-caused TLR4-dependent NF-κB activation in the Hep G 2 cells; PA also activated IRAKs, which were inhibited by celastrol. Knocking down IRAKs abolished PA-caused NF-κB activation. the first time show that targeting IRAKs is one way in which celastrol inhibits NF-κB activation.