Activation of Mitogen-activated Protein Kinase Pathways Induces Antioxidant Response Element-mediated Gene Expression via a Nrf2-dependent Mechanism

Yu, Rong; Chen, Chi; Mo, Yin Yuan; Hebbar, Vidya; Owuor, Edward D.; Tan, Tse‐Hua; Kong, Ah‐Ng

doi:10.1074/jbc.m004037200

Cited by 324 publications

(221 citation statements)

References 36 publications

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“…Because primary human mesangial cells are not efficiently transfected with plasmid expression vectors, HeLa cells were transfected with the Nrf2 plasmid expression vector LNCX-Nrf2. This vector activated the Nrf2/antioxidant response pathway, measured as increased production of HO-1 [16], and also increased IL-8 production 2.5-fold compared to an empty LNCX vector (data not shown).…”

Section: Resultsmentioning

confidence: 93%

Activation of the Nrf2/antioxidant response pathway increases IL-8 expression

Zhang

Chen²,

Song

et al. 2005

Eur. J. Immunol.

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Section: Resultsmentioning

confidence: 93%

Activation of the Nrf2/antioxidant response pathway increases IL-8 expression

Zhang

Chen²,

Song

et al. 2005

Eur. J. Immunol.

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“…Nrf2 activation and its binding to ARE sites in the promoter region are critical in HO-1 expression in human hepatoma HepG2, MCF-7 mammary epithelial, and microglial cells (Alam et al, 2000;Min et al, 2006;Yu et al, 2000). Adenosine also activated Nrf2, as evident from its translocation to the nuclei and increase in Nrf2-ARE binding, which appears important in HO-1 expression in microglia (Figs.…”

Section: Discussionmentioning

confidence: 92%

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Min

Kim

Jou

et al. 2008

Glia

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Adenosine, a purine nucleoside, has been reported to suppress the inflammatory responses of microglia in the brain. However, the underlying mechanisms of its anti-inflammatory action are unclear at present. Here we show that adenosine reduces the increase in intracellular reactive oxygen species (ROS) through expression of an antioxidant enzyme, hemeoxygenase-1 (HO-1). The H 2 O 2 -induced intracellular ROS level was significantly low in microglia pretreated with adenosine for 3-6 h, compared with that in untreated cells. Adenosine induced HO-1 mRNA and protein expression within 3 h, which was maintained for up to 12 h. Nuclear factor E2-related factor 2 (Nrf2), a transcription factor, and phosphatidylinositol 3-kinase (PI3K) and Akt pathways appear to mediate HO-1 expression. In response to adenosine, Nrf2 translocated from the cytosol to nuclei, and bound to the antioxidant response element (ARE). Adenosine enhanced HO-1 promoter activity in an ARE-dependent manner. Moreover, the nucleoside stimulated Akt phosphorylation, and suppressors of PI3K (LY294002 and wortmannin) reduced adenosine-induced HO-1 expression. However, we propose that the effects of adenosine are independent of adenosine receptors, since agonists and antagonists of A1, A2a, and A3 had little effect on the regulation of intracellular ROS and HO-1 expression. Our results collectively suggest that adenosine acts as an endogenous regulator of brain inflammation via modulation of microglial ROS production. V

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“…Inactive Nrf 2 is localized in the cytoplasm, in part or totally, as a consequence of binding to cytoskeleton-associated protein, Keap1. 31 Recently, it has also been reported that MAP kinases, including ERKs, JNKs, and p38, are implicated in phosphorylation and stabilization of Nrf2 to facilitate its nuclear translocation 32 and binding to distinct but very similar DNA elements, individually or alternatively referred to as Maf recognition element (MARE), 33 stress-response element (StRE), 29 or antioxidant-response element (ARE). 34 In addition, PI3K/Akt signaling pathway also regulates AREs activation via the nuclear translocation of Nrf2.…”

Section: Discussionmentioning

confidence: 99%

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Kim

et al. 2006

Cell Death Differ

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We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GSTl-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.

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Activation of Mitogen-activated Protein Kinase Pathways Induces Antioxidant Response Element-mediated Gene Expression via a Nrf2-dependent Mechanism

Cited by 324 publications

References 36 publications

Activation of the Nrf2/antioxidant response pathway increases IL-8 expression

Activation of the Nrf2/antioxidant response pathway increases IL-8 expression

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

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