Endoplasmic reticulum stress increases inflammatory responses by bronchial epithelial cells

Airway epithelial cells (AEC) provide a first line of defense against respiratory pathogens. Their main function is to provide a physical barrier. In addition these cells display and mediate a tolerant phenotype towards microbial products, e.g. LPS, in the pulmonary system. Contradictory, an important proinflammatory function of AECs during pulmonary inflammatory processes has been demonstrated in the literature. Recently, several pulmonary diseases have been correlated with the unfolded protein response (UPR). UPR is an essential adaptive intracellular signalling pathway activated in response to accumulation of un- or misfolded proteins (ER-Stress). UPRhas been shown to have proinflammatory potential. Therefore we wondered whether the tolerant phenotype of AECs could be reverted during conditions of ER stress.  Induction of UPR by Thapsigargin resulted in an increased response of Beas2B cells to LPS with respect to IL-6 and IL-8 induction, indicating a hyperactive phenotype. These observations could be confirmed using differentiated murine tracheal epithelial cells cultivated in air-liquid interface. UPR induction resulted in an increase of p38 and ERK phosphorylation by LPS, however NFκB activation was not significantly affected. The importance of p38 and ERK activation were further verified using pharmacological inhibitors. Investigating which ER-stress sensor mediates this process we could demonstrate that PERK is critically important for the LPS and UPR mediated increase in IL6 and IL8 expression. Taken together our results indicate that ER-stress is able to reverse the tolerant phenotype of AECs and this process might be of crucial importance in several pulmonary diseases.