Abstract
BackgroundAllergic asthma is characterized by airway inflammation in response to antigen exposure, leading to airway remodeling and lung dysfunction. Epithelial-mesenchymal transition (EMT) may play a role in airway remodeling through the acquisition of a mesenchymal phenotype in airway epithelial cells. TGF-β1 is known to promote EMT; however, other cytokines expressed in severe asthma with extensive remodeling, such as IL-22, may also contribute to this process. In this study, we evaluated the contribution of IL-22 to EMT in primary bronchial epithelial cells from healthy and asthmatic subjects.MethodsPrimary bronchial epithelial cells were isolated from healthy subjects, mild asthmatics and severe asthmatics (n=5 patients per group). The mRNA and protein expression of epithelial and mesenchymal cell markers and EMT-associated transcription factors was evaluated following stimulation with TGF-β1, IL-22 and TGF-β1+IL-22.ResultsPrimary bronchial epithelial cells stimulated with TGF-β1 underwent EMT, demonstrated by decreased expression of epithelial markers (E-cadherin and MUC5AC) and increased expression of mesenchymal markers (N-cadherin and vimentin) and EMT-associated transcription factors. IL-22 alone had no effect on epithelial or mesenchymal gene expression. However, IL-22+TGF-β1 promoted the expression of some EMT transcription factors (Snail1 and Zeb1) and led to a more profound cadherin shift, but only in cells obtained from severe asthmatics.ConclusionThe impact of IL-22 on airway epithelial cells depends on the cytokine milieu and the clinical phenotype of the patient. Further studies are required to determine the molecular mechanism of IL-22 and TGF-β1 cooperativity in driving EMT in primary human bronchial epithelial cells.
Highlights
Inflammation in allergic asthma reflects complex activation of the adaptive and innate immune systems [1]
As previous reports have demonstrated that IL-17A promotes Epithelial-mesenchymal transition (EMT) in airway epithelial cells in a TGF-β1-dependent manner [22] and contributes to airway remodeling in a mouse model of allergic airway inflammation [23], the aim of this study was to elucidate the in vitro impact of IL-22 in conjunction with TGF-β1 on the induction of a mesenchymal phenotype in primary human bronchial epithelial cells derived from healthy control subjects and patients with either mild or severe allergic asthma
Sections were stained by immunohistochemistry for the expression of IL-22 (Figure 1B-C), demonstrating a significantly greater influx of IL-22 expressing cells in the bronchi of severe asthmatics compared to mild asthmatics and healthy controls (Figure 1E; p < 0.05)
Summary
Inflammation in allergic asthma reflects complex activation of the adaptive and innate immune systems [1]. A recent study in a mouse model of chronic house dust mite-driven allergic airway inflammation demonstrated the capacity of airway epithelial cells to acquire mesenchymal characteristics under these conditions [21]. This process was associated with increased airway smooth muscle mass and elevated TGF-β1 signalling in the lung. As previous reports have demonstrated that IL-17A promotes EMT in airway epithelial cells in a TGF-β1-dependent manner [22] and contributes to airway remodeling in a mouse model of allergic airway inflammation [23], the aim of this study was to elucidate the in vitro impact of IL-22 in conjunction with TGF-β1 on the induction of a mesenchymal phenotype in primary human bronchial epithelial cells derived from healthy control subjects and patients with either mild or severe allergic asthma. We evaluated the contribution of IL-22 to EMT in primary bronchial epithelial cells from healthy and asthmatic subjects
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