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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 AMPK? knockdown with siRNA revealed that Nrf2 nuclear accumulation and subsequent binding to the ferritin H ARE induced by resveratrol were dependent on activation of AMPK?, but not PI3K/AKT. Furthermore, AMPK? knockdown blocked resveratrol-induced phosphorylation of glycogen synthase kinase 3? (GSK3?) at Ser9 as well as ARE-dependent transcriptional activation of the ferritin H and HO-1 genes, suggesting that AMPK? is an upstream kinase for GSK3? phosphorylation and activation of the Nrf2-ARE pathway. Consistently, GSK3? knockdown by siRNA enhanced resveratrol-mediated ferritin H mRNA induction, and the inhibition of AMPK? 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 AMPK? 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:Activators of AMP-activated protein kinase (AMPK) increase the expression of the human microsomal fatty acid ?-hydroxylase CYP4F2. A 24-h treatment of either primary human hepatocytes or the human hepatoma cell line HepG2 with 5-aminoimidazole-4-carboxamide-1-?-D-ribofuranoside (AICAR), which is converted to 5-aminoimidazole-4-carboxamide-1-?-D-ribofuranosyl 5'-monophosphate, an activator of AMPK, caused an average 2.5- or 7-fold increase, respectively, of CYP4F2 mRNA expression but not of CYP4A11 or CYP4F3, CYP4F11, and CYP4F12 mRNA. Activation of CYP4F2 expression by AICAR was significantly reduced in HepG2 cells by an AMPK inhibitor, 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyrrazolo[1,5-a]-pyrimidine (compound C) or by transfection with small interfering RNAs for AMPK? isoforms ?1 and ?2. A 2.5-fold increase in CYP4F2 mRNA expression was observed upon treatment of HepG2 cells with 6,7-dihydro-4-hydroxy-3-(2'-hydroxy[1,1'-biphenyl]-4-yl)-6-oxo-thieno[2,3-b]pyridine-5-carbonitrile (A-769662), a direct activator for AMPK. In addition, the indirect activators of AMPK, genistein and resveratrol increased CYP4F2 mRNA expression in HepG2 cells. Pretreatment with compound C or 1,2-dihydro-3H-naphtho[2,1-b]pyran-3-one (splitomicin), an inhibitor of the NAD(+) activated deacetylase SIRT1, only partially blocked activation of CYP4F2 expression by resveratrol, suggesting that a SIRT1/AMPK-independent pathway also contributes to increased CYP4F2 expression. Compound C greatly diminished genistein activation of CYP4F2 expression. 7H-benz[de]benzimidazo[2,1-a]isoquinoline-7-one-3-carboxylic acid acetate (STO-609), a calmodulin kinase kinase (CaMKK) inhibitor, reduced the level of expression of CYP4F2 elicited by genistein, suggesting that CaMKK activation contributed to AMPK activation by genistein. Transient transfection studies in HepG2 cells with reporter constructs containing the CYP4F2 proximal promoter demonstrated that AICAR, genistein, and resveratrol stimulated transcription of the reporter gene. These results suggest that activation of AMPK by cellular stress and endocrine or pharmacologic stimulation is likely to activate CYP4F2 gene expression.

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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