Abstract
Several studies show that bronchial epithelial cells (pBEC) from asthma patients display exaggerated production of cytokines and chemokines.We found that pBEC from mild asthmatics can release enhanced levels of IL-8, IL-6, G-CSF when stimulated with TNF-α and IL-17A, compared to pBEC from most healthy individuals. pBEC producing exaggerated amounts were termed as hyperresponsive pBEC, compared to normoresponsive pBEC with low amounts.Hyperresponsive pBEC as opposed to normoresponsive pBEC are unresponsive to corticosteroids. This study aims to reveal the underlying molecular defect leading to hyperresponsive pBEC.
Previously we showed that IL-17 attenuates microRNA16 (miR16) expression, resulting in IL-8 mRNA stabilization in lung cell lines by modulating AU-binding proteins that bind to AU-rich elements in IL-8 mRNA. In hyperresponsive pBEC from mild asthmatics, stimulations with TNF-α and IL-17A induced elevated levels of miR16, but we found no differences in IL-8 mRNA half-life. Hence, we hypothesize miR16 accumulation may relate to translational control, as this is also dependent on AU-rich elements. We explored the role of specific translational repressors like TiAR (T-cell internal antigen receptor) in pBEC. Notably, TiAR failed to translocate to the cytoplasm in hyperresponsive pBEC by western blotting and confocal microscopy. This indicates reduced translational repression, resulting in enhanced IL-8 and IL-6 production.
So, hyperresponsive PBEC in asthma patients may have a defect in translational repression. Macrophages and monocytes (not shown) do not show this hyperresponsiveness. We currently aim to clarify why TiAR responds differently.
This abstract has been presented previously at the European Respiratory Society's Lung Science Conference in March 2016.
- Copyright ©the authors 2016