A shift in the IL-6/STAT3 signalling pathway imbalance towards the SHP2 pathway in severe asthma results in reduced proliferation process

Abstract Background Bronchial fibroblastsare the main structural cells responsible for extracellular matrix production and turnover in lung tissue. They play a key role in airway remodelling in asthma through different cytokines including interleukin (IL-6). Objective To decipher IL-6 signalling in bronchial fibroblastsobtained from severe eosinophilic asthmatics compared to mild asthmatics and healthy controls. Methods Human bronchial fibroblastswere isolated from bronchial biopsies of mild and severe eosinophilic asthmatics and non-atopic healthy controls. IL-6 was assessed by qRT-PCR and ELISA. Phosphorylated STAT3, SHP2 and p38/MAPK were evaluated by Western blot. Chemical inhibitors for SHP2 and p38 were used. Fibroblastproliferation was evaluated by BrdU incorporation test. Results IL-6 release was significantly increased in fibroblastsfrom mild and severe asthmatics compared to healthy controls. Fibroblastsfrom severe asthmatics showed a reduced STAT3activation compared to mild asthmatics and healthy controls. Constitutive activation of phosphatase SHP2 was found to negatively regulate IL-6 induced STAT3phosphorylation in fibroblastsfrom severe asthmatics. This effect was accompanied by a decrease in fibroblastproliferation rate due to the activated p38/mitogen-activated protein kinase. SHP2 and p38/MAPK specific inhibitors (PHPS1 and SB212190) significantly induce a restoration of STAT3phosphorylation, IL-6 target gene expression and cell proliferation. Conclusion These data show dysregulated IL-6 signalling in bronchial fibroblastsderived from severe eosinophilic asthmatic subjects involving the protein tyrosine phosphataseSHP2 and p38MAPK. Collectively, our data provides new insights into the mechanisms by which bronchial fibroblastsregulate airway remodelling in severe asthma.