Mast cells regulate procollagen I (α1) production by bronchial fibroblasts derived from subjects with asthma through IL-4/IL-4δ2 ratio

Background: Asthma is characterized by inflammation and remodeling. Mast cells are generally increased in bronchial mucosa of subjects with asthma. These cells release a wide variety of cytokines and mediators that have the capacity to stimulate other resident cells such as smooth muscle cells and fibroblasts. Objective: This study was designed to evaluate whether mast cells modulate collagen production by bronchial fibroblasts isolated from subjects with asthma and normal subjects through cytokine production. Methods: Human mast cells were cocultured for 72 hours with primary bronchial fibroblasts isolated from bronchial biopsies of subjects with mild asthma and normal controls. Procollagen I (alpha(1)), IL-4R alpha, IL-13R alpha(1), and IL-13R alpha(2) gene expression by bronchial fibroblasts and IL-4 and IL-4 delta 2 gene expression by mast cells were quantified by real-time RT-PCR. IL-4 production was also measured by ELISA in culture supernatants. Results: Procollagen I (oil) gene expression by fibroblasts from subjects with asthma was significantly higher compared with cells from normal controls when cocultured with mast cells. Mast cells expressed IL-4 isoform and IL-4 delta 2, an alternative splice variant of IL-4. Coculture significantly increased the expression of IL-4 but not IL-4 delta 2 by mast cells when they were cultured with fibroblasts from subjects with asthma compared with cells from normal controls. Neutralization of IL-4 abrogated collagen mRNA expression. There was no significant change in IL-4R alpha or IL-13R alpha(1). However, IL-13R alpha(2) gene expression was significantly reduced in fibroblasts from subjects with asthma. Conclusion: These results suggest that inflammatory process may regulate airway remodelling through crosstalk between inflammatory and structural cells. Targeting this crosstalk may have therapeutic application. Clinical implications: Understanding mechanisms that govern airway remodeling and collagen deposition in asthma is a step toward therapeutic management of this disease. In this work, we found that mast cell-fibroblast crosstalk may be a potential future target to control some aspects of airway remodeling.