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: 2.3). 02/2009; 380(3):449-53. DOI: 10.1016/j.bbrc.2009.01.082
Source: PubMed


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 · 3.71 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 03/2014; 34(1). DOI:10.1002/jat.2827 · 2.98 Impact Factor
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    • "However, upon oxidant condition, Nrf2 dissociates from Keap1, translocates to the nucleus, and binds to antioxidant response element (ARE) and regulates the transcription of antioxidant proteins including heme oxygenase-1 (HO-1) (Lee et al., 2011a). Activation of Nrf2 in microglia has been shown to exert neuroprotective influences by inhibiting pro-inflammatory cytokines (Koh et al., 2009). In addition, it was reported that Nrf2 knockout mice were hypersensitive to the neuro-inflammation induced by lipopolysaccharide (LPS) (Innamorato et al., 2008). "
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    ABSTRACT: 3,4,5-Trihydroxycinnamic acid (THC) is a derivative of hydroxycinnamic acids, which have been reported to possess a variety of biological properties such as anti-inflammatory, anti-tumor, and neuroprotective activities. However, biological activity of THC has not been extensively examined. Recently, we reported that THC possesses anti-inflammatory activity in LPS-stimulated BV2 microglial cells. However, its precise mechanism by which THC exerts anti-inflammatory action has not been clearly identified. Therefore, the present study was carried out to understand the anti-inflammatory mechanism of THC in BV2 microglial cells. THC effectively suppressed the LPS-induced induction of pro-inflammatory mediators such as NO, TNF-α, and IL-1β. THC also suppressed expression of MCP-1, which plays a key role in the migration of activated microglia. To understand the underlying mechanism by which THC exerts these anti-inflammatory properties, involvement of Nrf2, which is a cytoprotective transcription factor, was examined. THC resulted in increased phosphorylation of Nrf2 with consequent expression of HO-1 in a concentration-dependent manner. THC-induced phosphorylation of Nrf2 was blocked with SB203580, a p38 MAPK inhibitor, indicating that p38 MAPK is the responsible kinase for the phosphorylation of Nrf2. Taken together, the present study for the first time demonstrates that THC exerts anti-inflammatory properties through the activation of Nrf2 in BV2 microglial cells, suggesting that THC might be a valuable therapeutic adjuvant for the treatment of inflammation-related disorders in the CNS.
    Biomolecules and Therapeutics 01/2013; 21(1):60-5. DOI:10.4062/biomolther.2012.091 · 1.73 Impact Factor
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