AhR-dependent secretion of PDGF-BB by human classically activated macrophages exposed to DEP extracts stimulates lung fibroblast proliferation

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 tha...

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Bibliographic Details
Published in:Toxicology and applied pharmacology 2015-06, Vol.285 (3), p.170-178
Main Authors: Jaguin, Marie, Fardel, Olivier, Lecureur, Valérie
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
AIR POLLUTION
Aryl hydrocarbon receptor
Benzo(a)pyrene - toxicity
Cell Line, Tumor
Cell Proliferation
Diesel exhaust particles
DISEASES
FIBROBLASTS
Fibroblasts - cytology
FIBROSIS
GENES
GROWTH FACTORS
Humans
INDUCTION
Life Sciences
LIGANDS
Lung fibroblasts
LUNGS
Macrophage polarization
MACROPHAGES
Macrophages - drug effects
Macrophages - metabolism
PARTICLES
PHOSPHORYLATION
Platelet Derived Growth Factor-beta (PDGF-B)
POLARIZATION
POLLUTANTS
Polychlorinated Dibenzodioxins - toxicity
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins c-sis - secretion
PYRENE
RECEPTORS
Receptors, Aryl Hydrocarbon - metabolism
SECRETION
TYROSINE
Tyrphostins - pharmacology
Vehicle Emissions - toxicity
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Summary: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. [Display omitted] •PDGF-B expression and secretion are increased by DEPe exposure in human M1 and M2 MΦ.•DEPe-induced PDGF-B expression is aryl-hydrocarbon-dependent.•DEPe-exposed M1 MΦ secrete sufficient PDGF-B to increase lung fibroblast proliferation.
ISSN:0041-008X
1096-0333
DOI:10.1016/j.taap.2015.04.007