Interleukin-8 induction by the environmental contaminant benzo(a)pyrene is aryl hydrocarbon receptor-dependent and leads to lung inflammation.
Benzo(a)pyrene (BP) is an environmental contaminant known to favor airway inflammation likely through up-regulation of pro-inflammatory cytokines. The present study was designed to characterize its effects toward interleukin-8 (IL-8), a well-established pulmonary inflammatory cytokine. In primary human macrophages, BP was shown to induce IL-8 expression at both mRNA and secretion levels in a dose-dependent manner. Such an up-regulation was likely linked to aryl hydrocarbon receptor (AhR)-activation since BP-mediated IL-8 induction was reduced after AhR expression knock-down through RNA interference. Moreover, electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation experiments showed BP-triggered binding of AhR to a consensus xenobiotic responsive element (XRE) found in the human IL-8 promoter. Finally, BP administration to mice led to over-expression of keratinocyte chemoattractant (KC), the murine functional homologue of IL-8, in lung. It also triggered the recruitment of neutrophils in bronchoalveolar lavage (BAL) fluids, which was however fully abolished in the presence of a chemical antagonist of the KC/IL-8 receptors CXCR1/CXCR2, thus supporting the functional and crucial involvement of KC in BP-induced lung inflammation. Overall, these data highlight an AhR-dependent regulation of IL-8 in response to BP that likely contributes to the airway inflammatory effects of this environmental chemical.
Podechard
Normand
N
UMR-INSERM U620, Team Toxicity of Polycyclic Aromatic Hydrocarbons (labellisée Ligue contre le Cancer), IFR140, Université de Rennes 1, France.
Lecureur
Valérie
V
Le Ferrec
Eric
E
Guenon
Isabelle
I
Sparfel
Lydie
L
Gilot
David
D
Gordon
John R
JR
Lagente
Vincent
V
Fardel
Olivier
O
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002465:Cell Movement; D002630:Chemotactic Factors / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced* / Q000276:immunology; D034622:RNA Interference; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D020218:Response Elements; D015854:Up-Regulation
D002630:Chemotactic Factors; D004785:Environmental Pollutants; D016209:Interleukin-8; D018336:Receptors, Aryl Hydrocarbon; D023063:Receptors, Interleukin-8B; D001564:Benzo(a)pyrene