Abstract
BackgroundAirway inflammation is an important characteristic of asthma and has been associated with airway remodelling and bronchial hyperreactivity. The mucosal microenvironment composed of structural cells and highly specialised extracellular matrix is able to amplify and promote inflammation. This microenvironment leads to the development and maintenance of a specific adaptive response characterized by Th2 and Th17. Bronchial fibroblasts produce multiple mediators that may play a role in maintaining and amplifying this response in asthma.ObjectiveTo investigate the role of bronchial fibroblasts obtained from asthmatic subjects and healthy controls in regulating Th17 response by creating a local micro-environment that promotes this response in the airways.MethodsHuman bronchial fibroblasts and CD4+T cells were isolated from atopic asthmatics and non-atopic healthy controls. CD4+T were co-cultured with bronchial fibroblasts of asthmatic subjects and healthy controls. RORc gene expression was detected by qPCR. Phosphorylated STAT-3 and RORγt were evaluated by western blots. Th17 phenotype was measured by flow cytometry. IL-22, IL17, IL-6 TGF-β and IL1-β were assessed by qPCR and ELISA.ResultsCo-culture of CD4+T cells with bronchial fibroblasts significantly stimulated RORc expression and induced a significant increase in Th17 cells as characterized by the percentage of IL-17+/CCR6+ staining in asthmatic conditions. IL-17 and IL-22 were increased in both normal and asthmatic conditions with a significantly higher amount in asthmatics compared to controls. IL-6, IL-1β, TGF-β and IL-23 were significantly elevated in fibroblasts from asthmatic subjects upon co-culture with CD4+T cells. IL-23 stimulates IL-6 and IL-1β expression by bronchial fibroblasts.ConclusionInteraction between bronchial fibroblasts and T cells seems to promote specifically Th17 cells profile in asthma. These results suggest that cellular interaction particularly between T cells and fibroblasts may play a pivotal role in the regulation of the inflammatory response in asthma.
Highlights
Th17 cells are distinct population of CD4+ T cells that produce IL-17A, IL-17F and IL-22 [1,2] and are involved in the pathogenesis of a variety of inflammatory conditions including experimental autoimmune encephalomyelitis, collagen-induced arthritis, psoriasis, allergy and asthma [3,4,5,6,7,8]
We investigated the role of bronchial fibroblasts obtained from asthmatic subjects and healthy controls in regulating Th17 response by creating a local microenvironment that promotes this response in the airways
RORc mRNA significantly increased in T cells after co-culture with both bronchial fibroblasts from asthmatic (0.06 ± 0.04 for T cells alone to 1.79 ± 0.30 mRNA relative expression when cocultured with asthmatic fibroblasts; p=0.00005) and healthy subjects (0.06 ± 0.05 for T cells alone to 1.12 ± 0.22 mRNA relative expression when co-cultured with healthy fibroblasts; p=0.0005)
Summary
Th17 cells are distinct population of CD4+ T cells that produce IL-17A, IL-17F and IL-22 [1,2] and are involved in the pathogenesis of a variety of inflammatory conditions including experimental autoimmune encephalomyelitis, collagen-induced arthritis, psoriasis, allergy and asthma [3,4,5,6,7,8]. The mucosal microenvironment composed of structural cells and highly specialised extracellular matrix (ECM) is able to amplify and promote inflammation in the airways. In vitro and animal studies showed that interactions of inflammatory cells with structural cells play an important role in airway inflammation and remodelling [12,13]. The mucosal microenvironment composed of structural cells and highly specialised extracellular matrix is able to amplify and promote inflammation. This microenvironment leads to the development and maintenance of a specific adaptive response characterized by Th2 and Th17. Results: Co-culture of CD4+T cells with bronchial fibroblasts significantly stimulated RORc expression and induced a significant increase in Th17 cells as characterized by the percentage of IL-17+/CCR6+ staining in asthmatic conditions. These results suggest that cellular interaction between T cells and fibroblasts may play a pivotal role in the regulation of the inflammatory response in asthma
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