IL-1β augments TGF-β inducing epithelial-mesenchymal transition of epithelial cells and associates with poor pulmonary function improvement in neutrophilic asthmatics

Background: Neutrophilic asthmatics (NA) have less response to inhaled corticosteroids. We aimed to find out the predictor of treatment response in NA. Methods: Asthmatics (n = 115) and healthy controls (n = 28) underwent clinical assessment during 6-month follow-up with standardized therapy. Asthmatics were categorized by sputum differential cell count. The mRNA expressions were measured by RT-qPCR for sputum cytokines (IFN-gamma, IL-1 beta, IL-27, FOXP3, IL-17A, and IL-5). The protein of IL-1 beta in sputum supernatant was detected by ELISA. Reticular basement membranes (RBM) were measured in the biopsy samples. The role and signaling pathways of IL-1 beta mediating the epithelial-mesenchymal transition (EMT) process were explored through A549 cells. Results: NA had increased baseline sputum cell IL-1 beta expression compared to eosinophilic asthmatics (EA). After follow-up, NA had less improvement in-FEV1 compared to EA. For all asthmatics, sputum IL-1 beta mRNA was positively correlated with protein expression. Sputum IL-1 beta mRNA and protein levels were negatively correlated to FEV1 improvement. After subgrouping, the correlation between IL-1 beta mRNA and FEV1 improvement was significant in NA but not in EA. Thickness of RBM in asthmatics was greater than that of healthy controls and positively correlated with neutrophil percentage in bronchoalveolar lavage fluid. In vitro experiments, the process of IL-1 beta augmenting TGF-beta 1-induced EMT cannot be abrogated by glucocorticoid or montelukast sodium, but can be reversed by MAPK inhibitors. Conclusions: IL-1 beta level in baseline sputum predicts the poor lung function improvement in NA. The potential mechanism may be related to IL-1 beta augmenting TGF-beta 1-induced steroid-resistant EMT through MAPK signaling pathways.

Automated summary

Neutrophilic asthmatics (NA) show less improvement in lung function after treatment, which is associated with increased IL-1β levels in sputum. Additionally, IL-1β may enhance steroid-resistant EMT induced by TGF-β1 via the MAPK signaling pathway.