ERK-dependent induction of TNFalpha expression by the environmental contaminant benzo(a)pyrene in primary human macrophages.
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.
Lecureur
Valérie
V
INSERM U620, Faculté de Pharmacie, 2 avenue du Pr. Léon Bernard, 35043 Rennes, France. valerie.lecureur@univ-rennes1.fr
Ferrec
Eric Le
EL
N'diaye
Monique
M
Vee
Marc Le
ML
Gardyn
Claire
C
Gilot
David
D
Fardel
Olivier
O
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
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