title: Activation of interleukin-6 and -8 expressions by methylmercury in human U937 macrophages involves RelA and p50.
abstract: The accumulation of macrophages has been observed around lesions of the brain in patients with Minamata disease. In this condition, mercury has been detected histochemically in macrophages throughout the brain. However, the role of macrophages in the neurotoxicity of methylmercury (MeHg) and the molecular mechanisms of their response to MeHg exposure remain to be elucidated. Here, we investigated how MeHg affects the expression of proinflammatory cytokines such as interleukin (IL)-6 and IL-8 in cultured human U937 macrophages. Compared with controls, IL-6 and IL-8 mRNA expression was maximally induced in U937 macrophages after treatment with 10 μM MeHg for 6 h. The protein secretion of IL-6 and IL-8 was significantly stimulated by MeHg in U937 macrophages. Results from luciferase reporter assay indicated functional activation of nuclear factor kappa B and the involvement of subunit RelA and p50 in MeHg-induced IL-6 and IL-8 activation, which was confirmed by siRNA knockdown experiments. MeHg exposure at 4 μM also significantly induced IL-8 expression in U-87 MG cells at mRNA and protein level, indicating that IL-8 induction might be a general mode of action of MeHg treatment among different cell types. These results indicate a possible involvement of an early inflammatory response, including IL-6 and IL-8 expression in the pathogenesis of MeHg. N-acetyl-l-cysteine suppressed MeHg-induced activation of IL-6 and IL-8 mRNA expression in U937 macrophages, indicating the effectiveness of N-acetyl-l-cysteine as a therapeutic drug in MeHg-induced inflammation. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Integrated Physiology Section, Department of Basic Medical Science, National Institute for Minamata Disease, 4058-18 Hama, Minamata, Kumamoto, 867-0008, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Noureen
authors.initials: N
authors.lastname: Khan
authors.affiliation: Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Muflihatul
authors.initials: M
authors.lastname: Muniroh
authors.affiliation: Integrated Physiology Section, Department of Basic Medical Science, National Institute for Minamata Disease, 4058-18 Hama, Minamata, Kumamoto, 867-0008, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Motomura
authors.affiliation: Integrated Physiology Section, Department of Basic Medical Science, National Institute for Minamata Disease, 4058-18 Hama, Minamata, Kumamoto, 867-0008, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Yanagisawa
authors.affiliation: Department of Immunology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Takami
authors.initials: T
authors.lastname: Matsuyama
authors.affiliation: Department of Environmental Toxicology and Center for Health and the Environment, University of California, Davis, CA, 95616, USA.
authors.forename: Christoph F A
authors.initials: CF
authors.lastname: Vogel
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects*; D008767:Methylmercury Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells
chemical_list: C508606:CXCL8 protein, human; D016166:Free Radical Scavengers; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D008767:Methylmercury Compounds; D051267:NF-E2-Related Factor 2; D052002:NF-kappa B p50 Subunit; C495635:NFE2L2 protein, human; C498143:RELA protein, human; D051996:Transcription Factor RelA; D000111:Acetylcysteine
keywords: N-acetyl-l-cysteine; NF-κB; RelA; inflammation; interleukin-6; interleukin-8; macrophage; methylmercury; p50