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J. Biol. Chem., Vol. 281, Issue 29, 19906-19915, July 21, 2006

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Aryl Hydrocarbon Receptor- and Calcium-dependent Induction of the Chemokine CCL1 by the Environmental Contaminant Benzo[a]pyrene^*

Monique N'Diaye¹, Eric Le Ferrec², Dominique Lagadic-Gossmann, Sébastien Corre, David Gilot, Valérie Lecureur, Patricia Monteiro¹, Claudine Rauch, Marie-Dominique Galibert, and Olivier Fardel^¶

From the INSERM U620, and CNRS, Unité Mixte de Recherche 6061, Laboratoire de Génétique et Développement, Facultéde Médecine, Université de Rennes 1, IFR140, 2 Avenue du Pr. Léon Bernard, 35043 Rennes Cedex and the ^¶Département Hématologie Immunologie et Thérapie Cellulaire, Centre Hospitalier Universitaire, 35033 Rennes Cedex, France

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed immunotoxic environmental contaminants well known to regulate expression of pro-inflammatory cytokines such as interleukine-1 and tumor necrosis factor-. In the present study, we demonstrated that the chemokine CCL1, notably involved in cardiovascular diseases and inflammatory or allergic processes, constitutes a new molecular target for PAHs. Indeed, exposure to PAHs such as benzo[a]pyrene (BP) markedly increased mRNA expression and secretion of CCL1 in primary human macrophage cultures. Moreover, intranasal administration of BP to mice enhanced mRNA levels of TCA3, the mouse orthologue of CCL1, in lung. CCL1 induction in cultured human macrophages was fully prevented by targeting the aryl hydrocarbon receptor (AhR) through chemical inhibition or small interfering RNA-mediated down-modulation of its expression. In addition, BP and the potent AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin were found to enhance activity of a CCL1 promoter sequence containing a consensus xenobiotic-responsive element known to specifically interact with AhR. Moreover, 2,3,7,8-tetrachlorodibenzo-p-dioxin triggered AhR binding to this CCL1 promoter element as revealed by chromatin immunoprecipitation experiments and electrophoretic mobility shift assays. In an attempt to further characterize the mechanism of CCL1 induction, we demonstrated that BP was able to induce an early and transient increase of intracellular calcium concentration in human macrophages. Inhibition of this calcium increase, using the calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester or the calcium store-operated channel inhibitor 2-aminoethoxydiphenyl borate, fully blocked CCL1 up-regulation. Taken together, these results bring the first demonstration that PAHs induce expression of the chemokine CCL1 in an AhR- and calcium-dependent manner.

Received for publication, February 7, 2006 , and in revised form, April 27, 2006.

^* This work was supported in part by Agence Française de Sécurité Sanitaire de L' Environnement et du Travail and the Fondation de France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipients of fellowships from the Ligue Nationale contre le Cancer.

² To whom correspondence should be addressed. Tel.: 33-02-23-23-47-17; Fax: 33-02-23-23-47-94; E-mail: eric.leferrec{at}univ-rennes1.fr.

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