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tBHQ inhibits LPS-induced microglial activation via Nrf2-mediated suppression of p38 phosphorylation

School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
Biochemical and Biophysical Research Communications (Impact Factor: 2.28). 02/2009; 380(3):449-53. DOI: 10.1016/j.bbrc.2009.01.082
Source: PubMed

ABSTRACT Role of microglial Nrf2 activation in preventing neuronal death caused by microglial hyperactivation is investigated by using BV-2 microglial cells as modulator and primary neurons as target. Pretreatment of microglial cells with tBHQ, a phenolic antioxidant activating Nrf2, attenuated the LPS-derived overproduction of pro-inflammatory neurotoxic mediators like TNF-alpha, IL-1beta, IL-6, PGE(2), and NO as well as the morphological changes associated with microglial hyperactivation. Pretreatment of BV-2 cells with tBHQ suppressed LPS-induced phosphorylation of p38 required for overproduction of neurotoxic mediators. Results obtained using Nrf2-specific shRNA showed that expression of Nrf2 in microglia plays a critical role in tBHQ-derived suppression of LPS-induced p38 phosphorylation and microglial hyperactivation. Conditioned culture media taken from LPS-stimulated microglia cause neuronal death. However, the conditioned media taken from tBHQ-pretreated and LPS-stimulated microglia did not cause death of primary neurons. This suggested that prior activation of Nrf2 in microglia may inhibit microglial hyperactivation and prevent neuronal death.

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    • "As such, decreased NF-κB activity partially explains the anti-inflammatory effect of tBHQ in the present study. These findings are consistent with previous studies showing that tBHQ or sulforaphane decreases NF-κB activation, production of inflammatory cytokines (TNF-α, IL-1β, and IL-6), COX-2 expression , and PGE2 release in vivo and in vitro (Heiss et al., 2001; Jin et al., 2010; Khodagholi and Tusi, 2011; Koh et al., 2009). However, to the best of our knowledge, the present study is the first to report the protective role of Nrf2 activation on toxicant-stimulated inflammatory responses in human placental cells. "
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    ABSTRACT: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants, and BDE-47 is a prevalent PBDE congener detected in human tissues. Exposure to PBDEs has been linked to adverse pregnancy outcomes in humans. Although the underlying mechanisms of adverse birth outcomes are poorly understood, critical roles for oxidative stress and inflammation are implicated. The present study investigated antioxidant responses in a human extravillous trophoblast cell line, HTR-8/SVneo, and examined the role of nuclear factor E2-related factor 2 (Nrf2), an antioxidative transcription factor, in BDE-47-induced inflammatory responses in the cells. Treatment of HTR-8/SVneo cells with 5, 10, 15, and 20μM BDE-47 for 24h increased intracellular glutathione (GSH) levels compared to solvent control. Treatment of HTR-8/SVneo cells with 20μM BDE-47 for 24h induced the antioxidant response element (ARE) activity, indicating Nrf2 transactivation by BDE-47 treatment, and resulted in differential expression of redox-sensitive genes compared to solvent control. Pretreatment with tert-butyl hydroquinone (tBHQ) or sulforaphane, known Nrf2 inducers, reduced BDE-47-stimulated IL-6 release with increased ARE reporter activity, reduced nuclear factor kappa B (NF-κB) reporter activity, increased GSH production, and stimulated expression of antioxidant genes compared to non-Nrf2 inducer pretreated groups, suggesting that Nrf2 may play a protective role against BDE-47-mediated inflammatory responses in HTR-8/SVneo cells. These results suggest that Nrf2 activation significantly attenuated BDE-47-induced IL-6 release by augmentation of cellular antioxidative system via upregulation of Nrf2 signaling pathways, and that Nrf2 induction may be a potential therapeutic target to reduce adverse pregnancy outcomes associated with toxicant-induced oxidative stress and inflammation.
    Toxicology and Applied Pharmacology 10/2014; 281(1). DOI:10.1016/j.taap.2014.09.015 · 3.63 Impact Factor
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    • "tert-Butylhydroquinone (tBHQ) is a synthetic food antioxidant that prevents oxidative deterioration of oil and fat content of foods (Gharavi et al., 2007). More importantly, tBHQ has been shown to exhibit several pharmacological effects, such as anti-oxidant, antiinflammatory , and anti-carcinogenic effects, especially for stomach cancers (Jin et al., 2010; Koh et al., 2009). One mechanism by which tBHQ exerts these effects, is through induction of phase II detoxification enzymes, including NAD(P)H: quinone oxidoreductase (NQO1), glutamate–cysteine ligase catalytic subunit (GCLC), glutamate–cysteine ligase modifier subunit (GCLM) and HO-1 (Rushmore and Kong, 2002; Xu et al., 2005). "
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    ABSTRACT: Osteoclasts (OCLs) are multinucleated bone-resorbing cells that are differentiated by receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Our recent studies have shown that heme-oxygenase-1 (HO-1), a stress-induced cytoprotective enzyme, plays an important role in OCL differentiation, although the pharmacological significance of this effect remains unknown. In this study, we investigated the effects of tert-butylhydroquinone (tBHQ), a pharmacological HO-1 inducer, on in vitro differentiation of bone marrow-derived macrophages (BMMs) or murine monocytic cell line RAW-D into OCLs. tBHQ inhibited the formation and the bone-resorbing activity of OCLs. Moreover, tBHQ treatment decreased the expression of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator of OCL differentiation, and of OCL markers transcriptionally regulated by NFATc1, such as Src and cathepsin K. In addition, tBHQ impaired phosphorylation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinase, Akt, and inhibitor of nuclear factor kappa B alpha (IκBα). Finally, we show that tBHQ inhibited the release of high mobility group box 1 (HMGB1), a recently identified activator of OCL differentiation. Thus, tBHQ inhibits OCL differentiation through the HO-1/HMGB1 pathways. Copyright © 2012 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 01/2014; 34(1). DOI:10.1002/jat.2827 · 3.17 Impact Factor
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    • "Nrf2 activation is probably a result of NF-␬B signaling, cytokine production , and oxidative stress associated with microglial activation. Nrf2 dampens LPS-induced microglial activation and lowers the production of proinflammatory cytokines in BV-2 cells (Koh et al., 2009, 2011; Lee et al., 2012). It is noteworthy that inhibition of NF-␬B in microglia using BAY 11-7082 resulted in the up-regulation of Nqo1 rather than down-regulation as would be expected if there was direct cross-talk between NF-␬B and Nrf2. "
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    ABSTRACT: ATP-binding cassette (ABC) efflux transporters, including the multidrug resistance protein 1 (Mdr1), breast cancer resistance protein (Bcrp), and multidrug resistance-associated proteins (Mrps) extrude chemicals from the brain. While ABC transporters are critical for blood-brain barrier integrity, less attention has been placed on the regulation of these proteins in brain parenchymal cells such as microglia. Prior studies demonstrate that inflammation following lipopolysaccharide (LPS) treatment alters transporter expression in the livers of mice. Here, we sought to determine the effects of inflammation on the expression and function of transporters in microglia. To test this, the expression and function of ABC efflux transport proteins were quantified in mouse BV-2 microglial cells in response to activation with LPS. Intracellular retention of fluorescent rhodamine 123, Hoechst 33342, and calcein AM was increased in LPS-treated microglia suggesting that the function of Mdr1, Bcrp, and Mrps were decreased, respectively. LPS reduced Mdr1, Bcrp, and Mrp4 mRNA and protein expression between 40 and 70%. Conversely, LPS increased expression of Mrp1 and Mrp5 mRNA and protein. Immunofluorescent staining confirmed reduced Bcrp and Mrp4 and elevated Mrp1 and Mrp5 protein in activated microglia. Pharmacological inhibition of NFκ-B transcriptional signaling attenuated down-regulation of Mdr1a mRNA and potentiated up-regulation of Mrp5 mRNA in LPS-treated cells. Together, these data suggest that LPS stimulates microglia and impairs efflux of prototypical ABC transporter substrates by altering mRNA and protein expression, in part through NF-κB signaling. Decreased transporter efflux function in microglia may lead to retention of toxic chemicals and aberrant cell-cell communication during neuroinflammation.
    Journal of Pharmacology and Experimental Therapeutics 08/2012; 343(3). DOI:10.1124/jpet.112.196543 · 3.86 Impact Factor
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