Abstract
We recently found that tumor necrosis factor-α (TNF-α) may be involved in neuronal cell death induced by methylmercury in the mouse brain. Here, we examined the cells involved in the induction of TNF-α expression by methylmercury in the mouse brain by in situ hybridization. TNF-α-expressing cells were found throughout the brain and were identified as microglia by immunostaining for ionized calcium binding adaptor molecule 1 (Iba1). Methylmercury induced TNF-α expression in mouse primary microglia and mouse microglial cell line BV2. Knockdown of apoptosis signal-regulating kinase 1 (ASK1), an inflammatory cytokine up-regulator that is responsible for reactive oxygen species (ROS), decreased methylmercury-induced TNF-α expression through decreased phosphorylation of p38 MAP kinase in BV2 cells. Suppression of methylmercury-induced reactive oxygen species (ROS) by antioxidant treatment largely abolished the induction of TNF-α expression and phosphorylation of p38 by methylmercury in BV2 cells. Finally, in mouse brain slices, the TNF-α antagonist (WP9QY) inhibited neuronal cell death induced by methylmercury, as did the p38 inhibitor SB203580 and liposomal clodronate (a microglia-depleting agent). These results indicate that methylmercury induces mitochondrial ROS that are involved in activation of the ASK1/p38 pathway in microglia and that this is associated with induction of TNF-α expression and neuronal cell death.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Brain / cytology
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Brain / pathology*
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Cell Line
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Clodronic Acid / pharmacology
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Disease Models, Animal
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Environmental Pollutants / administration & dosage
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Environmental Pollutants / toxicity
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Gene Knockdown Techniques
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Humans
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Imidazoles / pharmacology
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MAP Kinase Kinase Kinase 5 / genetics
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MAP Kinase Kinase Kinase 5 / metabolism
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / genetics
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Male
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Mercury Poisoning, Nervous System / etiology
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Mercury Poisoning, Nervous System / pathology*
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Methylmercury Compounds / administration & dosage
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Methylmercury Compounds / toxicity
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Mice
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Microglia / drug effects*
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Microglia / pathology
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Mitochondria / drug effects
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Mitochondria / metabolism
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Neurons / drug effects*
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Neurons / pathology
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Peptides, Cyclic / pharmacology
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Phosphorylation / drug effects
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Primary Cell Culture
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Pyridines / pharmacology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Environmental Pollutants
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Imidazoles
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Methylmercury Compounds
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Peptides, Cyclic
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Pyridines
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Tnf protein, mouse
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Tumor Necrosis Factor-alpha
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WP9QY peptide
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Clodronic Acid
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 5
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Map3k5 protein, mouse
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SB 203580
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methylmercuric chloride