The TAK1→IKKβ→TPL2→MKK1/MKK2 signaling cascade regulates IL-33 expression in Cystic Fibrosis airway epithelial cells following infection by Pseudomonas aeruginosa

• Main Authors: Raquel eFarias, Simon eRousseau
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2016-01-01
• Series: Frontiers in Cell and Developmental Biology
• Subjects: Pseudomonas aeruginosa; Toll-Like Receptors; ERK; MAPK; Airway epithelium
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fcell.2015.00087/full

In cystic fibrosis (CF), chronic respiratory infections result in an exaggerated and uncontrolled inflammatory response that ultimately lead to a decrease in pulmonary function. We have previously described the presence of the alarmin IL-33 in lung explants from CF patients. The signals regulating IL-33 expression in the airway epithelium following a gram-negative bacterial infection are currently unknown. Our objective was to characterize the pathways in CF airway epithelial cells (AECs) leading to an increase in IL-33 expression. We found that, in CF AECs expressing a deletion of a phenylalanine at position 508 of the gene coding for Cystic Fibrosis Transmembrane Conductance Regulator (CFTRdelF508), exposure to live Pseudomonas aeruginosa upregulates IL-33 via the TLR2 and TLR5 signalling pathways. This up-regulation can be partially or fully reverted by pre-incubating CFTRdelF508 AECs with a CFTR corrector (VX-809) and/or a CFTR potentiator (VX-770). Similarly, incubation with the CFTR corrector and/or the CFTR potentiator also decreased IL-8 expression in response to infection. Moreover, using different protein kinase inhibitors that target elements downstream of TLR signalling, we show that the TAK1→IKKβ→TPL2→MKK1/MKK2 pathway regulates IL-33 expression following an infection with P. aeruginosa. Our findings represent the first characterization of the signals regulating IL-33 expression in CF airway epithelial cells in response to a bacterial infection.