The Chemokine CCL2 Protects Against Methylmercury Neurotoxicity

Godefroy, David; Gosselin, Romain–Daniel; Yasutake, Akira; Fujimura, Masatake; Combadière, Christophe; Maury-Brachet, Régine; Laclau, M.; Rakwal, Randeep; Mélik-Parsadaniantz, Stéphane; Bourdineaud, Jean‐Paul; Rostène, William

doi:10.1093/toxsci/kfr252

Cited by 34 publications

(26 citation statements)

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“…Recent- ly, Godefroy et al (2012) reported that CCL2 functions defensively against methylmercury toxicity, although the underlying molecular mechanism is unknown. In future research, the detailed mechanisms underlying methylmercury induction of NF-κB activation and chemokine expression will be further explored, and perhaps reveal a novel mechanism of methylmercury neurotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Methylmercury induces CCL2 expression through activation of NF-κB in human 1321N1 astrocytes

et al. 2012

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-Methylmercury is an environmental pollutant that is toxic to the central nervous system; however, the molecular mechanisms underlying its toxicity remain unclear. Methylmercury increases expression of several chemokines in the cerebellum of mice treated with methylmercury. The present study analyzes the mechanism underlying methylmercury-induced chemokine expression using human 1321N1 astrocytes, and shows that methylmercury increases CCL2 expression in these cells. The transcription factor NF-κB is involved in the induction of chemokine expression. Methylmercury increased the level of the NF-κB p65 subunit in the nuclei of 1321N1 cells. The methylmercury-induced increase in CCL2 expression was significantly decreased by suppression of p65 expression by RNA interference. These results suggest that methylmercury induces chemokine expression through activation of NF-κB in human astrocytes.Key words: Methylmercury, Chemokine, CCL2, NF-κB Correspondence: Akira Naganuma (E-mail: naganuma@m.tohoku.ac.jp) LetterThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.37, No.6, 1275-1278 Vol. 37 No. 6 1275 facturer's protocol. Lentivirus was produced in HEK293T cells by co-transfection of the lentiviral vector pGIPZ encoding p65-shRNA and the Trans-Lentiviral Packaging Plasmid Mix (Thermo Fisher Scientific). 1321N1 cells were infected with lentivirus in the presence of polybrene (5 μg/ml) and selected in medium containing puromycin (1 μg/ml). The target sequence of p65 shRNA used was 5'-ACCATCAAGATCAATGGCT-3'. Quantitative real-time PCR (qPCR)Total RNA was isolated from cells using the Isogen II kit (Nippon Gene, Tokyo, Japan) according to the manufacturer's instructions. First-strand cDNA synthesis was carried out using the PrimeScript TM RT reagent kit (Takara, Shiga, Japan). qPCR was performed using SYBR Premix EX Taq (Takara) (Hwang et al., 2011a;Takahashi et al., 2011). PCR primers used were GAPDH, 5'-GGGGAAGCTTGTCAATGG-3' (sense) and 5'-GGCAGTGATGGCATGGACTC-3' (antisense); p65, 5'-CTGCAGTTTGATGATGAAGA-3' (sense) and 5'-TAGGCGAGTTATAGCCTCAG-3' (antisense); and CCL2, 5'-CATTGTGGCCAAGGAGATCTG-3' (sense) and 5'-CTTCGGAGTTTGGGTTTGCTT-3' (antisense). Levels of P65 and CCL2 mRNA were normalized to that of GAPDH. Enzyme-linked immunosorbent assay (ELISA)CCL2 secreted into culture medium was quantified using the Quantikine ELISA kit (R&D Systems, Minneapolis, MN, USA) according to the manufacturer's instructions. Preparation of nuclear and post-nuclear fractions1321N1 cells were lysed in ice-cold hypotonic buffer (10 mM HEPES-KOH [pH 7.9], 1.5 mM MgCl 2 , 10 mM KCl, 1 mM Dithiothreitol [DTT], 0.5 mM phenylmethylsulfonyl fluoride [PMSF]) containing protease inhibitors (Roche Applied Science, Indianapolis, IN, USA) and 10% Nonidet P-40, and centrifuged at 15,000 × g at 4°C. The supernatant (post-nuclear fraction) was removed, and the pellet was resuspended in nuclear lysis buffer (10 mM HEPES-KOH [pH 7.9], 400 mM NaCl, 0.2 mM EDTA, 1.5 mM MgCl 2 , 1 mM DTT, 5% glycerol) containing protease inhibitors (Roche App...

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Section: Resultsmentioning

confidence: 99%

Methylmercury induces CCL2 expression through activation of NF-κB in human 1321N1 astrocytes

et al. 2012

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“…Recently, an elevation of MCP-1 expression in response to MeHg exposure was observed in mice experiment (10 mg/kg/day for 7 days) [22] and human 1321N1 astrocytoma cells (10 μM for 6 h) [26]. It was also reported to work as an alert system for MeHg exposure, using MCP-1-knockout mice [18].…”

Section: Introductionmentioning

confidence: 99%

Suppression of methylmercury-induced IL-6 and MCP-1 expressions by N-acetylcysteine in U-87MG human astrocytoma cells

et al. 2015

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“…Cytokines play an important role in intercellular signaling, and over 100 types have been described, including tumor necrosis factor (TNF), transforming growth factor (TGF), interleukins, interferons, and chemokines1415. Recently, Rostene et al 16. reported the relationship between CCL2, a chemokine, and methylmercury toxicity.…”

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Methylmercury induces the expression of TNF-α selectively in the brain of mice

Iwai-Shimada

Takahashi

Kim

et al. 2016

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Methylmercury selectively damages the central nervous system (CNS). The tumor necrosis factor (TNF) superfamily includes representative cytokines that participate in the inflammatory response as well as cell survival, and apoptosis. In this study, we found that administration of methylmercury selectively induced TNF-α expression in the brain of mice. Although the accumulated mercury concentration in the liver and kidneys was greater than in the brain, TNF-α expression was induced to a greater extent in brain. Thus, it is possible that there may exist a selective mechanism by which methylmercury induces TNF-α expression in the brain. We also found that TNF-α expression was induced by methylmercury in C17.2 cells (mouse neural stem cells) and NF-κB may participate as a transcription factor in that induction. Further, we showed that the addition of TNF-α antagonist (WP9QY) reduced the toxicity of methylmercury to C17.2 cells. In contrast, the addition of recombinant TNF-α to the culture medium decreased the cell viability. We suggest that TNF-α may play a part in the selective damage of the CNS by methylmercury. Furthermore, our results indicate that the higher TNF-α expression induced by methylmercury maybe the cause of cell death, as TNF-α binds to its receptor after being released extracellularly.

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The Chemokine CCL2 Protects Against Methylmercury Neurotoxicity

Cited by 34 publications

References 35 publications

Methylmercury induces CCL2 expression through activation of NF-κB in human 1321N1 astrocytes

Methylmercury induces CCL2 expression through activation of NF-κB in human 1321N1 astrocytes

Suppression of methylmercury-induced IL-6 and MCP-1 expressions by N-acetylcysteine in U-87MG human astrocytoma cells

Methylmercury induces the expression of TNF-α selectively in the brain of mice

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