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

作　　者：Yu-fan Shen Xue Zhang Ying Wang Fan-fan Cao Georges Uzan Bin Peng Deng-hai Zhang 

机构地区：[1]Department of Clinical Laboratory Diagnostics, Postgraduate Education College, Ningxia Medical University [2]Sino-French Cooperative Central Laboratory, Shanghai Gongli Hospital, Second Military Medical University [3]U972, Inserm, Lavoisier Building, Paul Brousse Hospital

出　　处：《Journal of Integrative Medicine》2016年第3期203-208,共6页结合医学学报（英文版）

基　　金：the Shanghai Gongli Hospital Youth Project (No. 2014GLQN16 for YS and No. 2012GLQN09 for XZ);the Shanghai Pudong District Science and Technology Innovation Project (No. PKJ2013-Y03 for YW);the Shanghai Pudong Youth Talent Project in Medicine (No. PWRq2013-11 for FC);the Shanghai Yang Fan Project (No. 15YF1410800 for FC);the International Science & Technology Cooperation Project of China (Grant 2011DFB30010 for GU);the National Natural Science Foundation of China (No. 81102349 for BP and No. 81400793 for YW);the Shanghai Excellent Academic Leader in Medicine (No. XBR2011054 for DZ);the Shanghai Traditional Chinese Medicine Content Construction Innovation Project (No. ZY3-CCCX-3-7001 for DZ)

摘　　要：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（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.

关 键 词：CELASTROL interleukin-1 receptor-associated kinases nuclear factor-kappa B Toll-like receptor 4 HEPATOCYTES 

分 类 号：R285[医药卫生—中药学]