Abstract
Pollution, including polycyclic aromatic hydrocarbons (PAH), may contribute to increased prevalence of asthma. PAH can bind to the Aryl hydrocarbon Receptor (AhR), a transcription factor involved in Th17/Th22 type polarization. These cells produce IL17A and IL-22, which allow neutrophil recruitment, airway smooth muscle proliferation and tissue repair and remodeling. Increased IL-17 and IL-22 productions have been associated with asthma. We hypothesized that PAH might affect, through their effects on AhR, IL-17 and IL-22 production in allergic asthmatics. Activated peripheral blood mononuclear cells (PBMCs) from 16 nonallergic nonasthmatic (NA) and 16 intermittent allergic asthmatic (AA) subjects were incubated with PAH, and IL-17 and IL-22 productions were assessed. At baseline, activated PBMCs from AA exhibited an increased IL-17/IL-22 profile compared with NA subjects. Diesel exhaust particle (DEP)-PAH and Benzo[a]Pyrene (B[a]P) stimulation further increased IL-22 but decreased IL-17A production in both groups. The PAH-induced IL-22 levels in asthmatic patients were significantly higher than in healthy subjects. Among PBMCs, PAH-induced IL-22 expression originated principally from single IL-22- but not from IL-17- expressing CD4 T cells. The Th17 transcription factors RORA and RORC were down regulated, whereas AhR target gene CYP1A1 was upregulated. IL-22 induction by DEP-PAH was mainly dependent upon AhR whereas IL-22 induction by B[a]P was dependent upon activation of PI3K and JNK. Altogether, these data suggest that DEP-PAH and B[a]P may contribute to increased IL22 production in both healthy and asthmatic subjects through mechanisms involving both AhR -dependent and -independent pathways.
Highlights
Allergic asthma has strongly increased in the last decades in western countries and is considered mainly as a Th2 mediated disease
As there are some controversies about the effect of Aryl hydrocarbon Receptor (AhR) ligands on the production of IL-17 which may relate to the use of particular single cell types, we evaluated the effects of polycyclic aromatic hydrocarbons (PAH) in an environment where all these cell types are represented and can interact, in particular with dendritic cells, i.e. peripheral blood mononuclear cells (PBMCs)
To evaluate if this difference was found in PBMCs, Th17 type cytokine production was measured in anti-CD3/CD28 stimulated PBMCs
Summary
Allergic asthma has strongly increased in the last decades in western countries and is considered mainly as a Th2 mediated disease. There is increasing evidence that environmental pollution contributes to this augmented prevalence [1]. We and others have shown that Polycyclic Aromatic Hydrocarbons derived from diesel exhaust particles (DEP-PAH) play an inflammatory and adjuvant role in the development and exacerbation of allergic inflammation by skewing the immune response towards a Th2 profile [2,3,4,5]. It is clear that the biological response to many environmental pollutants is a direct consequence of their interactions with the Aryl hydrocarbon Receptor (AhR), a cytosolic transcription factor which binds exogenous ligands such as PAH or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), as well as endogenous ligands derived from tryptophane metabolism such as 6-formylindolo[3,2-b] carbazole (FICZ). In agreement with the presence of these endpoints in asthma, increased levels of IL-17A, IL-17F and IL-22 are found at the circulating and lung levels in allergic asthmatic patients as compared with controls [16,17,18]
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