title: AhR-dependent secretion of PDGF-BB by human classically activated macrophages exposed to DEP extracts stimulates lung fibroblast proliferation.
abstract: Lung diseases are aggravated by exposure to diesel exhaust particles (DEPs) found in air pollution. Macrophages are thought to play a crucial role in lung immune response to these pollutants, even if the mechanisms involved remain incompletely characterized. In the present study, we demonstrated that classically and alternative human macrophages (MΦ) exhibited increased secretion of PDGF-B in response to DEP extract (DEPe). This occurred via aryl hydrocarbon receptor (AhR)-activation because DEPe-induced PDGF-B overexpression was abrogated after AhR expression knock-down by RNA interference, in both M1 and M2 polarizing MΦ. In addition, TCDD and benzo(a)pyrene, two potent AhR ligands, also significantly increased mRNA expression of PDGF-B in M1 MΦ, whereas some weak ligands of AhR did not. We next evaluated the impact of conditioned media (CM) from MΦ culture exposed to DEPe or of recombinant PDGF-B onto lung fibroblast proliferation. The tyrosine kinase inhibitor, AG-1295, prevents phosphorylations of PDGF-Rβ, AKT and ERK1/2 and the proliferation of MRC-5 fibroblasts induced by recombinant PDGF-B and by CM from M1 polarizing MΦ, strongly suggesting that the PDGF-BB secreted by DEPe-exposed MΦ is sufficient to activate the PDGF-Rβ pathway of human lung fibroblasts. In conclusion, we demonstrated that human MΦ, whatever their polarization status, secrete PDGF-B in response to DEPe and that PDGF-B is a target gene of AhR. Therefore, induction of PDGF-B by DEP may participate in the deleterious effects towards human health triggered by such environmental urban contaminants.
authors.affiliation: UMR INSERM U1085, Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Université de Rennes 1, 2 Avenue du Pr Léon Bernard, 35043 Rennes Cedex, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Jaguin
authors.affiliation: UMR INSERM U1085, Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Université de Rennes 1, 2 Avenue du Pr Léon Bernard, 35043 Rennes Cedex, France; Pôle Biologie, Centre Hospitalier Universitaire (CHU) Rennes, 2 rue Henri Le Guilloux, 35033 Rennes Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
authors.affiliation: UMR INSERM U1085, Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), Université de Rennes 1, 2 Avenue du Pr Léon Bernard, 35043 Rennes Cedex, France. Electronic address: valerie.lecureur@univ-rennes1.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lecureur
mesh_terms: D000077214:Becaplermin; D001564:Benzo(a)pyrene / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005347:Fibroblasts / Q000166:cytology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: C407689:6,7-dimethoxy-2-phenylquinoxaline; D000072317:Polychlorinated Dibenzodioxins; D020574:Proto-Oncogene Proteins c-sis; D018336:Receptors, Aryl Hydrocarbon; D020032:Tyrphostins; D001335:Vehicle Emissions; D000077214:Becaplermin; D001564:Benzo(a)pyrene; D011505:Protein-Tyrosine Kinases
keywords: Aryl hydrocarbon receptor; Diesel exhaust particles; Lung fibroblasts; Macrophage polarization; Platelet Derived Growth Factor-beta (PDGF-B)