Role of AMP-activated protein kinase in ferritin H gene expression by resveratrol in human T cells.

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Iwasaki K, Ray PD, Huang BW, Sakamoto K, Kobayashi T, Tsuji Y

Role of AMP-activated protein kinase in ferritin H gene expression by resveratrol in human T cells.

Biochemistry. 2013 Jul 30;52(30):5075-83. doi: 10.1021/bi400399f. Epub 2013 Jul 16.

PubMed ID
23829535 [ View in PubMed
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Abstract

Resveratrol, a natural polyphenol, increases cellular antioxidant capacity by inducing the expression of a battery of cytoprotective genes through an antioxidant responsive element (ARE). However, upstream signaling events initiated by resveratrol leading to the activation of an ARE enhancer, particularly in immune cells, have not been fully elucidated. In this study, ARE-dependent transcriptional activation of the ferritin heavy chain (ferritin H) gene by resveratrol was further investigated in Jurkat T cells and human peripheral blood mononuclear cells. We found that AMP-activated protein kinase (AMPK) plays a key role in the activation of nuclear factor E2-related factor (Nrf2) and subsequent ARE-dependent ferritin H gene transcription by resveratrol. A chromatin immunoprecipitation assay for Nrf2 after AMPKalpha knockdown with siRNA revealed that Nrf2 nuclear accumulation and subsequent binding to the ferritin H ARE induced by resveratrol were dependent on activation of AMPKalpha, but not PI3K/AKT. Furthermore, AMPKalpha knockdown blocked resveratrol-induced phosphorylation of glycogen synthase kinase 3beta (GSK3beta) at Ser9 as well as ARE-dependent transcriptional activation of the ferritin H and HO-1 genes, suggesting that AMPKalpha is an upstream kinase for GSK3beta phosphorylation and activation of the Nrf2-ARE pathway. Consistently, GSK3beta knockdown by siRNA enhanced resveratrol-mediated ferritin H mRNA induction, and the inhibition of AMPKalpha by compound C or siRNA weakened the protective effect of resveratrol against oxidative stress-induced cytotoxicity in CD3+ T cells. Collectively, these results suggest that AMPKalpha plays a significant role in ARE-dependent transcription of ferritin H genes by resveratrol and may influence the redox status in immune cells.