Artemisinin Attenuates Lipopolysaccharide-Stimulated Proinflammatory Responses by Inhibiting NF-κB Pathway in Microglia Cells

Zhu, Cansheng; Xiong, Zhaojun; Chen, Xiaohong; Peng, Fuhua; Hu, Xueqiang; Chen, Yanming; Wang, Qing

doi:10.1371/journal.pone.0035125

Cited by 70 publications

(41 citation statements)

References 35 publications

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“…In this study, artemether has been shown to attenuate the production of NO/iNOS, PGE2/COX-2/mPGES-1, as well as the pro-inflammatory cytokines TNFα and IL-6. We therefore (2012) also showed that artemisinin inhibited IκB phosphorylation and p65 NF-κB translocation to the nucleus in LPS activated primary microglia cells [28]. It therefore appears that artemisinin derivatives, including artemether might be inhibiting LPSinduced neuroinflammation by targeting similar mechanisms involving the NF-κB signalling pathway.…”

Section: Activated Microglia Produce Various Pro-inflammatory Mediatomentioning

confidence: 88%

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

et al. 2015

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Artemether, a lipid-soluble derivative of artemisinin has been reported to possess anti-inflammatory properties. In this study, we have investigated the molecular mechanisms involved in the inhibition of neuroinflammation by the drug. The effects of artemether on neuroinflammation-mediated HT22 neuronal toxicity were also investigated in a BV2 microglia/HT22 neuron co-culture. To investigate effects on neuroinflammation, we used LPS-stimulated BV2 microglia treated with artemether (5-40µM) for 24 hours. ELISAs and western blotting were used to detect pro-inflammatory cytokines, nitric oxide, PGE2, iNOS, COX-2 and mPGES-1. BACE-1 activity and Aβ levels were measured with ELISA kits. Protein levels of targets in NF-κB and p38 MAPK signalling, as well as HO-1, NQO1 and Nrf2 were also measured with western blot. NF-κB binding to the DNA was investigated using EMSA. MTT, DNA fragmentation and ROS assays in BV2-HT22 neuronal co-culture were used to evaluate the effects of artemether on neuroinflammation-induced neuronal death. The role of Nrf2 in the anti-inflammatory activity of artemether was investigated in BV2 cells transfected with Nrf2 siRNA. Artemether significantly suppressed pro-inflammatory mediators (NO/iNOS, PGE2/COX-2/mPGES-1, TNFα, and IL-6), Aβ and BACE-1 in BV2 cells following LPS stimulation. These effects of artemether were shown to be mediated through inhibition of NF-κB and p38MAPK signalling. Artemether produced increased levels of HO-1, NQO1 and GSH in BV2 microglia. The drug activated Nrf2 activity by increasing nuclear translocation of Nrf2 and its binding to antioxidant response elements in BV2 cells. Transfection of BV2 microglia with Nrf2 siRNA resulted in the loss of both anti-inflammatory and neuroprotective activities of artemether. We conclude that artemether induces Nrf2 expression and suggest that Nrf2 mediates the anti-inflammatory effect of artemether in BV2 microglia. Our results suggest that this drug has a therapeutic potential in neurodegenerative disorders. 3 KeywordsArtemether, neuroinflammation, BV2 microglia, HT22 hippocampal neurons, NF-κB, Nrf2 4 BackgroundIn the central nervous system (CNS), the microglia plays an important role in immune defence and tissue repair [1]. Under normal conditions, these cells provide surveillance whilst maintaining homeostasis in the brain [2]. In response to injury, harmful toxins, infection or inflammation, microglial cells become activated, secreting pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), reactive oxygen/nitrogen species and pro-inflammatory cytokines including IL-6 and TNFα [3,4]. These pro-inflammatory mediators are mainly regulated by the transcription factor NF-κB [5]. NF-κB binds to the DNA and its transcriptional activity regulates several genes, which promote neuroinflammation. The p38 mitogenactivated protein kinase (p38 MAPK) signalling pathway also plays an important role in the expression and activity of pro-inflammatory cytokines in microglial cells [6][7][8].Excessive production o...

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Section: Activated Microglia Produce Various Pro-inflammatory Mediatomentioning

confidence: 88%

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

et al. 2015

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“…NF-κB, a pleiotropic regulator involved in microglial cell responses, can suppress the production of proinflammatory enzymes and cytokines, including NO, PGE2, TNF-α and IL-6 [13,24,34]. Under normal circumstances, NF-κB binds to IκB to form an inactive heterodimer in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Propofol attenuates intermittent hypoxia induced up-regulation of proinflammatory cytokines in microglia through inhibiting the activation of NF-Bκ/p38 MAPK signalling

Liu¹,

Sun²,

Lian³

et al. 2017

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A b s t r a c t As immune sentinels of the central nervous system (CNS), microglia is pivotal cellular mediator of neuroinflammatory processes. Activation of microglia might elicit the expression of proinflammatory cytokines involved in the progression of neuroinflammatory diseases. Numerous studies have demonstrated that propofol (2,6-diisopropylphenol) has an effective anti-inflammatory property. Intermittent hypoxia (IH), as a result of obstructive sleep apnoea (OSA), could lead to neuron damage and neuroinflammation in the CNS. Here, we determined the effects of propofol on the inflammatory response in microglia during IH. The levels of nuclear factor-κB (NF-κB) inhibitor (IκB) and activated p38 mitogen-activated protein kinase (MAPK) exposed to IH with or without propofol treatment were detected by Western blot. The viability of cells exposed to various concentrations of propofol was monitored with MTT assay. The production and mRNA levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were evaluated by qRT-PCR

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“…The increase in NFκB, JNK and c-Jun expression in microglia after LPS induction indicated that these pathways were involved in the LPS-induced activation. Similarly, NFκB and JNK/c-Jun pathways were demonstrated to be activated by LPS in microglia [5,6,7]. Secretion from MSC significantly reduced expression of these protein, which suggests that the reduction of proinflammatory cytokines and increase of anti-inflammatory cytokines may be mediated by these pathways.…”

Section: Discussionmentioning

confidence: 99%

“…In response to inflammation within the CNS, microglia are activated and they assume a phenotypic shift, including changes in morphology, and producing a barrage of proinflammatory [tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, nitric oxide (NO) and superoxide] and anti-inflammatory factors [IL-10, IL-13, transforming growth factor (TGF)-β)] and undergo rapid proliferation [2,3,4]. The activation of microglia has been suggested to be mediated by the NFκB and c-Jun N-terminal kinase (JNK) pathways [5,6,7]. Although, in general, microglia have a neuroprotective function, chronic activation of microglia has been implicated in the exacerbation of various neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and multiple sclerosis [2].…”

Section: Introductionmentioning

confidence: 99%

Paracrine Effects of Mesenchymal Stem Cells-Conditioned Medium on Microglial Cytokines Expression and Nitric Oxide Production

Ooi

Dheen

Tay³

2014

Neuroimmunomodulation

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Background/Aim: Microglia, the resident macrophages in the central nervous system, secrete various proinflammatory cytokines and undergo proliferation upon activation in various neurodegenerative diseases. Activation of microglia has been implicated in exacerbation of various neurodegenerative diseases. Recently, it has been proposed that mesenchymal stem cells (MSC) have immunosuppressive properties and the potential to moderate inflammation. This study aimed to elucidate the effects of MSC-conditioned medium (MSC-CM) in modulating microglial activation by analyzing microglial proinflammatory and anti-inflammatory factors [interleukin (IL)-6, tumor necrosis factor (TNF)-a, inducible nitric oxide synthase (iNOS) and IL-10], signaling pathway molecules [NFκB, c-Jun N-terminal kinase (JNK) and MKP-1) and NO production. Methods: Immortalized murine microglia cell line, BV2 microglia and primary microglia isolated from C57BL/6 mouse pup brains were used in this study. Mouse MSC were isolated from the male C57BL/6 mouse tibia and fibula. The effects of MSC-CM on the expression of inflammatory cytokines and signaling molecules in microglia were elucidated using RT-PCR, immunofluorescence analysis and Western blot analysis. NO production in microglia was assessed using a Griess kit. Results: MSC-CM significantly reduced the mRNA and protein expression levels of proinflammatory cytokines (IL-6 and TNF-a) in microglia activated by lipopolysaccharide (LPS). In addition, MSC-CM significantly reduced the protein expression of NFκB, JNK and c-Jun, but increased the expression levels of IL-10 and MKP-1 in activated BV2 microglia. NO production and iNOS expression by BV2 microglia in MSC-CM were increased. Conclusions: Overall, our findings suggest that MSC immunomodulate microglial activities through paracrine effects.

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Artemisinin Attenuates Lipopolysaccharide-Stimulated Proinflammatory Responses by Inhibiting NF-κB Pathway in Microglia Cells

Cited by 70 publications

References 35 publications

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

Propofol attenuates intermittent hypoxia induced up-regulation of proinflammatory cytokines in microglia through inhibiting the activation of NF-Bκ/p38 MAPK signalling

Paracrine Effects of Mesenchymal Stem Cells-Conditioned Medium on Microglial Cytokines Expression and Nitric Oxide Production

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