Interleukin-8 induction by the environmental contaminant benzo(a)pyrene is aryl hydrocarbon receptor-dependent and leads to lung inflammation
Introduction
Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BP) are ubiquitous environmental contaminants that originate from multiple sources, including diesel exhaust particles, tobacco smoke and air pollution, and to which humans, especially their respiratory tract, are commonly exposed (Hattemer-Frey and Travis, 1991). PAHs exert a wide range of toxic effects, including carcinogenic and pro-inflammatory effects in lung (Borm et al., 1997, Nel et al., 2001, Martey et al., 2005). These deleterious effects of these environmental chemicals have been linked, at least in part, to activation of the aryl hydrocarbon receptor (AhR) and to subsequent interaction of the heterodimer PAHs/AhR/AhR nuclear translocator (ARNT), with specific xenobiotic responsive elements (XREs) found in the 5′-flanking region of PAH-regulated genes, including cytochromes P-450 (CYP) 1A1/2 and CYP1B1 genes (Nebert et al., 2004).
Adverse inflammatory effects due to PAHs towards the respiratory system are well-established (Nel et al., 2001). Stimulations of cytokines/chemokines relevant to airway inflammation are probably involved; the role of AhR in these regulations and their exact contribution to lung inflammation remain however to be precised. To gain insights about these points in the present study, we have studied the regulation of the chemokine interleukin-8 (IL-8) and of its functional mouse homologue keratinocyte chemoattractant (KC) by PAHs since (i) IL-8 is a major target of PAH-containing diesel particles (Kawasaki et al., 2001, Pei et al., 2002) and (ii) IL-8 and KC, via interacting with their receptors CXCR1/CXCR2, play an important role in the pathogenesis of airway inflammation through the chemoattraction of neutrophils (Luster, 1998).
Using primary human macrophages known to mimic alveolar macrophages (Akagawa, 2002), we demonstrated that BP, known as a prototypical PAH, enhanced IL-8 production in an AhR-dependent manner. Moreover intranasal administration (i.n.) of BP to mouse resulted in activated KC expression in lung associated with the development of inflammation, which was, however, fully prevented by using a chemical antagonist of CXCR1/CXCR2. Such data therefore establish IL-8/KC as PAH targets likely contributing in a major way to airway inflammation triggered by exposure to these environmental contaminants.
Section snippets
Chemicals
BP, benzo(e)pyrene (BeP), tricaprylin and N-acetylcysteine (NAC) were provided by Sigma–Aldrich (St Louis, MO) whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was obtained from Cambridge Isotope Laboratories (Cambridge, MA). Pifithrin-α (PFTα), Bay-11-7082 and NF-κB activation inhibitor were purchased from Calbiochem (La Jolla, CA). 3′-methoxy-4′-nitroflavone (3′M4′NF) was a kind gift from Dr. T. Gasiewicz (University of Rochester Medical Center, Rochester). CXCL8(3–72)K11R/G31P is a potent
BP-induced IL-8 expression and secretion in primary human macrophages
BP was found to trigger up-regulation of IL-8 mRNA expression and IL-8 secretion in primary macrophages in a dose-dependent manner. Its effect started from 1 μM and reached a maximum at 2–10 μM (Fig. 1A and B). Low BP doses such as 0.1 μM had no or only minimal effect on IL-8 expression, at both mRNA and protein levels (Fig. 1A and B). mRNA expression of CYP1B1, a well-known PAH-regulated gene (Nebert et al., 2004), was up-regulated in a dose-dependent manner similar to that observed for IL-8 mRNA
Discussion
The data reported in the present study showed that IL-8 is a target of PAHs such as BP via AhR activation in primary human macrophages and that the increase of secretion of its murine functional homologue KC is crucial to BP-induced lung inflammation. Interestingly, IL-8 induction in macrophages occurred after a relatively low dose (1 μM) and short-time treatment with BP, indicating that acute and transient exposure to PAHs may be sufficient to enhance IL-8 secretion. Such an up-regulation of
Acknowledgements
We wish to thank Dr. L. Vernhet, Dr. D. Lagadic-Gossmann and Dr. S. Corre for helpful comments, and C. Morzadec, C. Le Quément and M. Le Vée for expert technical assistance.
This work was supported by grants from the “Agence Française de Sécurité Sanitaire de l’Environnement et du Travail” (AFSSET), the “Fondation de France” and the “Ligue Nationale contre le Cancer”. N. Podechard is a recipient of a fellowship from the Région Bretagne.
References (41)
- et al.
Health effects of air pollution
J. Allergy Clin. Immunol.
(2004) - et al.
The diesel exhaust component pyrene induces expression of IL-8 but not of eotaxin
Int. Immunopharmacol.
(2003) - et al.
Leukocyte migration and activation by murine chemokines
Immunobiology
(1996) - et al.
The environmental carcinogen benzo[a]pyrene induces expression of monocyte-chemoattractant protein-1 in vascular tissue: a possible role in atherogenesis
Mutat. Res.
(2007) - et al.
ERK-dependent induction of TNFalpha expression by the environmental contaminant benzo(a)pyrene in primary human macrophages
FEBS Lett.
(2005) - et al.
CXCL8((3-73))K11R/G31P antagonizes ligand binding to the neutrophil CXCR1 and CXCR2 receptors and cellular responses to CXCL8/IL-8
Biochem. Biophys. Res. Commun.
(2002) - et al.
Aryl hydrocarbon receptor- and calcium-dependent induction of the chemokine CCL1 by the environmental contaminant benzo[a]pyrene
J. Biol. Chem.
(2006) - et al.
Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer
J. Biol. Chem.
(2004) - et al.
Polycyclic aromatic hydrocarbons induce IL-8 expression through nuclear factor kappaB activation in A549 cell line
Cytokine
(2002) - et al.
MEK is a key modulator for TLR5-induced interleukin-8 and MIP3alpha gene expression in non-transformed human colonic epithelial cells
J. Biol. Chem.
(2004)
Regulation of subcellular localization of the aryl hydrocarbon receptor (AhR)
Arch. Biochem. Biophys.
Characterization of the activated form of the aryl hydrocarbon receptor in the nucleus of HeLa cells in the absence of exogenous ligand
Arch. Biochem. Biophys.
Induction of CYP1A1 gene expression in mouse hepatoma cells by benzo[e]pyrene, a ligand of the 4S polycyclic hydrocarbon-binding protein
Toxicol. Appl. Pharmacol.
Cytochrome P450-dependent toxicity of environmental polycyclic aromatic hydrocarbons towards human macrophages
Biochem. Biophys. Res. Commun.
Modulation of the chemokines KC and MCP-1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice
Arch. Biochem. Biophys.
Functional heterogeneity of colony-stimulating factor-induced human monocyte-derived macrophages
Int. J. Hematol.
Neutrophils amplify the formation of DNA adducts by benzo[a]pyrene in lung target cells
Environ. Health Perspect.
The selective phosphodiesterase 4 inhibitor RP 73–401 reduced matrix metalloproteinase 9 activity and transforming growth factor-beta release during acute lung injury in mice: the role of the balance between tumor necrosis factor-alpha and interleukin-10
J. Pharmacol. Exp. Ther.
Redox signalling
Mol. Cell Biochem.
The combined CXCR1/CXCR2 antagonist CXCL8(3–74)K11R/G31P blocks neutrophil infiltration, pyrexia, and pulmonary vascular pathology in endotoxemic animals
J. Leukoc. Biol.
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