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

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 AMPKα knockdown with siRNA revealed that Nrf2 nuclear accumulation and subsequent binding to the ferritin H ARE induced by resveratrol were dependent on activation of AMPKα, but not PI3K/AKT. Furthermore, AMPKα knockdown blocked resveratrol-induced phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser9 as well as ARE-dependent transcriptional activation of the ferritin H and HO-1 genes, suggesting that AMPKα is an upstream kinase for GSK3β phosphorylation and activation of the Nrf2-ARE pathway. Consistently, GSK3β knockdown by siRNA enhanced resveratrol-mediated ferritin H mRNA induction, and the inhibition of AMPKα 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 AMPKα plays a significant role in ARE-dependent transcription of ferritin H genes by resveratrol and may influence the redox status in immune cells.

SUBMITTER: Iwasaki K

PROVIDER: S-EPMC4108177 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

Iwasaki Kenta K Ray Paul D PD Huang Bo-Wen BW Sakamoto Kensuke K Kobayashi Takaaki T Tsuji Yoshiaki Y

Biochemistry 20130716 30

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 ...[more]

PMID: 23829535

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Project description:Despite the promising effects of resveratrol, its efficacy in the clinic remains controversial. We were the first group to report that the SIRT1 activator resveratrol activates AMP-activated protein kinase (AMPK) (Diabetes 2005; 54: A383), and we think that the variability of this cascade may be responsible for the inconsistency of resveratrol's effects. Our current studies suggest that the effect of SIRT1 activators such as resveratrol may not be solely through activation of SIRT1, but also through an integrated effect of SIRT1-liver kinase B1 (LKB1)-AMPK. In this context, resveratrol activates SIRT1 (1) by directly binding to SIRT1; and (2) by increasing NAD⁺ levels by upregulating the salvage pathway through Nampt activation, an effect mediated by AMPK. The first mechanism promotes deacetylation of a limited number of SIRT1 substrate proteins (e.g., PGC-1). The second mechanism (which may be more important than the first) activates other sirtuins in addition to SIRT1, which affects a broad spectrum of substrates. Despite these findings, detailed mechanisms of how resveratrol activates AMPK have not been reported. Here, we show that (1) resveratrol-induced activation of AMPK requires the presence of functional LKB1; (2) Resveratrol increases LKB1 activity, which involves translocation and phosphorylation at T336 and S428; (3) Activation of LKB1 causes proteasomal degradation of LKB1; (4) At high concentrations (50-100 µM), resveratrol also activates AMPK through increasing AMP levels; and (5) The above-mentioned activation mechanisms vary among cell types, and in some cell types, resveratrol fails to activate AMPK. These results suggest that resveratrol-induced activation of AMPK is not a ubiquitous phenomenon. In addition, AMPK-mediated increases in NAD⁺ in the second mechanism require several ATPs, which may not be available in many pathological conditions. These phenomena may explain why resveratrol is not always consistently beneficial in a clinical setting.

Dataset Information

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

Publications

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

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