Transcription factor Nrf2 suppresses LPS-induced hyperactivation of BV-2 microglial cells

Koh, Kyungmi; Kim, Jaekyoon; Jang, Young Jin; Yoon, Keejung; Cha, Young‐Nam; Lee, Hyong Joo; Kim, Jiyoung

doi:10.1016/j.jneuroim.2011.01.004

Cited by 31 publications

(25 citation statements)

References 25 publications

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“…According to Li et al [2], accumulation of reactive oxygen and nitrogen species generated by inflammatory cells that is one of the mechanisms through which chronic inflammation contributes to diseases. The Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a redox sensitive transcription factor and a critical regulator of endogenous inducible defence systems in the body [3,4]. Under physiological conditions, Nrf2 is sequestered in the cytoplasm by the regulatory protein Kelch-like ECH-associated protein 1 (Keap1) [3,5].…”

Section: Introductionmentioning

confidence: 99%

“…The Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a redox sensitive transcription factor and a critical regulator of endogenous inducible defence systems in the body [3,4]. Under physiological conditions, Nrf2 is sequestered in the cytoplasm by the regulatory protein Kelch-like ECH-associated protein 1 (Keap1) [3,5]. However, in response to oxidative stress, Nrf2 translocates to the nucleus and binds to anti-oxidant response elements (ARE) in the DNA, to initiate transcription of cytoprotective genes [4].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of neuroinflammation in BV2 microglia by the biflavonoid kolaviron is dependent on the Nrf2/ARE antioxidant protective mechanism

et al. 2016

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of neuroinflammation in BV2 microglia by the biflavonoid kolaviron is dependent on the Nrf2/ARE antioxidant protective mechanism

et al. 2016

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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(Koh et al, , 2011Lee 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.…”

mentioning

confidence: 95%

Inflammatory Regulation of ATP Binding Cassette Efflux Transporter Expression and Function in Microglia

Gibson

Hossain

Richardson

et al. 2012

J Pharmacol Exp Ther

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ATP-binding cassette (ABC) efflux transporters, including multidrug resistance protein 1 (Mdr1), breast cancer resistance protein (Bcrp), and multidrug resistance-associated proteins (Mrps) extrude chemicals from the brain. Although 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 after 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 acetoxymethyl ester was increased in LPS-treated microglia, suggesting that the functions 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 nuclear factor B (NF-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-B signaling. Decreased transporter efflux function in microglia may lead to the retention of toxic chemicals and aberrant cell-cell communication during neuroinflammation.

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“…Some have been shown to dampen inflammation by activating the Nrf2 pathway (26,31,65). Our studies revealed a GCL-dependent mechanism underlying the anti-inflammatory effects of DMP against a LPS challenge.…”

Section: C and E Representative Blots For P-jnk (A) P-erk (C) Amentioning

confidence: 57%

“…The redox homeostasis in cells can alter inflammatory cytokine release, where a reducing redox potential inhibits and an oxidizing redox potential increases cytokine release (28 -30). Activation of the nuclear factor Nrf2 (erythroid-derived 2-like 2) antioxidant pathway, which up-regulates GSH biosynthesis along with a host of other effects, has also been shown to exert an anti-inflammatory effect (26,31). Efforts to increase de novo biosynthesis of GSH via small molecule activators of the Nrf2 pathway are a common therapeutic avenue (32,33).…”

mentioning

confidence: 99%

Post-translational Activation of Glutamate Cysteine Ligase with Dimercaprol

McElroy

Hari

Day

et al. 2017

Journal of Biological Chemistry

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Edited by F. Anne StephensonNeuroinflammation and oxidative stress are hallmarks of various neurological diseases. However, whether and how the redox processes control neuroinflammation is incompletely understood. We hypothesized that increasing cellular glutathione (GSH) levels would inhibit neuroinflammation. A series of thiol compounds were identified to elevate cellular GSH levels by a novel approach (i.e. post-translational activation of glutamate cysteine ligase (GCL), the rate-limiting enzyme in GSH biosynthesis). These small thiol-containing compounds were examined for their ability to increase intracellular GSH levels in a murine microglial cell line (BV2), of which dimercaprol (2,3-dimercapto-1-propanol (DMP)) was found to be the most effective compound. DMP increased GCL activity and decreased LPS-induced production of pro-inflammatory cytokines and inducible nitric-oxide synthase induction in BV2 cells in a concentration-dependent manner. The ability of DMP to elevate GSH levels and attenuate LPS-induced pro-inflammatory cytokine production was inhibited by buthionine sulfoximine, an inhibitor of GCL. DMP increased the expression of GCL holoenzyme without altering the expression of its subunits or Nrf2 target proteins (NQO1 and HO-1), suggesting a post-translational mechanism. DMP attenuated LPS-induced MAPK activation in BV2 cells, suggesting the MAPK pathway as the signaling mechanism underlying the effect of DMP. Finally, the ability of DMP to increase GSH via GCL activation was observed in mixed cerebrocortical cultures and N27 dopaminergic cells. Together, the data demonstrate a novel mechanism of GSH elevation by posttranslational activation of GCL. Post-translational activation of GCL offers a novel targeted approach to control inflammation in chronic neuronal disorders associated with impaired adaptive responses.

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Transcription factor Nrf2 suppresses LPS-induced hyperactivation of BV-2 microglial cells

Cited by 31 publications

References 25 publications

Inhibition of neuroinflammation in BV2 microglia by the biflavonoid kolaviron is dependent on the Nrf2/ARE antioxidant protective mechanism

Inhibition of neuroinflammation in BV2 microglia by the biflavonoid kolaviron is dependent on the Nrf2/ARE antioxidant protective mechanism

Inflammatory Regulation of ATP Binding Cassette Efflux Transporter Expression and Function in Microglia

Post-translational Activation of Glutamate Cysteine Ligase with Dimercaprol

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