Research Papers:

Isoliquiritigenin suppresses human T Lymphocyte activation via covalently binding cysteine 46 of IκB kinase

Fenggen Yan, Fen Yang, Rui Wang, Xiao Jun Yao, Liping Bai, Xing Zeng, JiaJun Huang, Vincent Kam Wai Wong, Christopher Wai Kei Lam, Hua Zhou, Xiaohui Su, Juan Liu, Ting Li and Liang Liu _

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Oncotarget. 2017; 8:34223-34235. https://doi.org/10.18632/oncotarget.11934

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Fenggen Yan1, Fen Yang1, Rui Wang1, Xiao Jun Yao1, Liping Bai1, Xing Zeng2, JiaJun Huang1, Vincent Kam Wai Wong1, Christopher Wai Kei Lam1, Hua Zhou1, Xiaohui Su1, Juan Liu1, Ting Li1, Liang Liu1

1State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China

2Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China

Correspondence to:

Liang Liu, email: [email protected]

Ting Li, email: [email protected]

Keywords: isoliquiritigenin, IKKβ, cysteine 46, T lymphocyte, immune-suppression

Received: February 25, 2016     Accepted: July 27, 2016     Published: September 10, 2016


The efficacious practice of precision personalized medicine requires a more exact understanding of the molecular mechanisms of drug, hence then it is necessary to identify the binding site of the drugs derived from natural sources. In the study, we investigated the suppressive effect and underlying mechanism of isoliquiritigenin (2′,4′,4-trihydroxychalcone; ILG), a phyto-flavonoid, on human T lymphocyte activation in vitro and in vivo. The results showed that ILG dose-dependently suppressed human T cell activation via suppressing IκBα phosphorylation and degradation, NF-κB nuclear translocation and IKKβ activity. Molecular docking results predicted that cysteine 46 (Cys-46) is probably the binding site of ILG on IKKβ, and this prediction has been validated by competition assay and kinase assay. To further verify the binding site of this compound in vivo, IKKβC46A transgenic (IKKβC46A) mice were generated. We found that ILG had a less potent immune-suppressive effect in homozygous IKKβC46A mice than IKKβ wild type (IKKβ wt) littermates with the delay-type hypersensitivity (DTH), suggesting that ILG cannot significantly suppress the inflammation due to the mutation of Cys-46 in the transgenic mice. Collectively, our findings indicate that the ILG inhibited T cell activation in vivo and in vitro via directly binding to IKKβ Cys46.

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