title: ERK-dependent induction of TNFalpha expression by the environmental contaminant benzo(a)pyrene in primary human macrophages.
abstract: Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BP) are toxic environmental contaminants known to enhance production of pro-inflammatory cytokines such as IL-1beta. The present study was designed in order to determine whether TNFalpha, another cytokine acting in inflammation, may also constitute a target for these chemicals. Both TNFalpha mRNA and TNFalpha secretion levels were found to be enhanced in human BP-treated macrophages. Dioxin, a contaminant activating the aryl hydrocarbon receptor (AhR) like PAHs, was also shown to increase TNFalpha expression. BP-mediated TNFalpha induction was however not suppressed by AhR antagonists, making unlikely the involvement of the typical AhR signalling pathway. BP-exposure of macrophages did not enhance NF-kappaB DNA binding activity, but it activated the MAP kinase ERK1/2. In addition, the use of chemical inhibitors of extracellular signal-regulated protein kinase (ERK) activation fully abrogated induction of TNFalpha production in BP-treated macrophages. These data likely indicate that PAHs enhance TNFalpha expression in human macrophages through an ERK-related mechanism. Such a regulation may contribute to confer pro-inflammatory properties to these widely-distributed environmental contaminants.
authors.affiliation: INSERM U620, Faculté de Pharmacie, 2 avenue du Pr. Léon Bernard, 35043 Rennes, France. valerie.lecureur@univ-rennes1.fr
authors.forename: Valérie
authors.initials: V
authors.lastname: Lecureur
authors.forename: Eric Le
authors.initials: EL
authors.lastname: Ferrec
authors.forename: Monique
authors.initials: M
authors.lastname: N'diaye
authors.forename: Marc Le
authors.initials: ML
authors.lastname: Vee
authors.forename: Claire
authors.initials: C
authors.lastname: Gardyn
authors.forename: David
authors.initials: D
authors.lastname: Gilot
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
mesh_terms: D001564:Benzo(a)pyrene / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004785:Environmental Pollutants / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D002070:Butadienes; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D005419:Flavonoids; D016328:NF-kappa B; D009570:Nitriles; D000072317:Polychlorinated Dibenzodioxins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D001564:Benzo(a)pyrene; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one