ERK-dependent induction of TNFα 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-1β. The present study was designed in order to determine whether TNFα, another cytokine acting in inflammation, may also constitute a target for these chemicals. Both TNFα mRNA and TNFα 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 TNFα expression. BP-mediated TNFα 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-κB 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 TNFα production in BP-treated macrophages. These data likely indicate that PAHs enhance TNFα 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.