Understanding the role of IGFALS in moderate-severe allergic asthma

<bold>Background:</bold> IGFALS forms a complex with insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) and is upregulated in moderate-severe asthma. However, as other leucine-rich proteins (e.g., CD14/TLR4), IGFALS could have also IGF-independent functions; for instance, on human bronchial epithelial cells (BECs). The aim of the present work was to explore the biological role of IGFALS in promoting the epithelial-mesenchymal transition (EMT), an event that may play a role in airways remodelling and severe asthma. <bold>Methods:</bold> We cultured a human BEC line (BEAS-2B) in BEGM medium with either classical inducers of EMT (TGF-β, LPS) or IGFALS at different concentrations. In addition, specific inhibitors of TGF-β (SB-431542) and TLR4 (TAK-242) pathways were combined with IGFALS (n=3-4). EMT markers were followed by different techniques. <bold>Results:</bold> IGFALS reduced the levels of E-cadherin with a similar dose-response to LPS (ED50: 0.24 and 0.56 μg/mL, respectively) in the BEAS-2B cell line, starting at a dose of 0.1 μg/mL. IGFALS potentiated E-cadherin downmodulation caused by suboptimal amounts of classical EMT inducers (TGF-β, LPS), but no synergic effect was observed. Finally, E-cadherin loss induced by IGFALS was blocked when a specific inhibitor of the TLR4 signalling pathway (but not the TGF-β signalling route) was added. <bold>Conclusions:</bold> Our results suggest a potential biological role of IGFALS in EMT and therefore airway remodelling, which match with the elevation of this protein in serum samples from moderate-severe allergic asthma patients previously detected by iTRAQ LC-MS/MS and ELISA. In addition, our preliminary data indicates that IGFALS could be signalling through the TLR4 pathway.