The TAK1→IKKβ→TPL2→MKK1/MKK2 Signaling Cascade Regulates IL-33 Expression in Cystic Fibrosis Airway Epithelial Cells Following Infection by Pseudomonas aeruginosa

被引:9
作者
Farias, Raquel [1 ]
Rousseau, Simon [1 ]
机构
[1] McGill Univ, Hth Ctr, Dept Med, Meakins Christie Labs,Res Inst, Montreal, PQ, Canada
关键词
MAPK; ERK; Toll-like receptor; airway epithelium; Pseudomonas aeruginosa; PULMONARY-FUNCTION; ACTIVATION; KINASE; INFLAMMATION; LIPOPOLYSACCHARIDE; INTERLEUKIN-33; IDENTIFICATION; MATURATION; RECEPTORS; CYTOKINE;
D O I
10.3389/fcell.2015.00087
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 signaling 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 signaling, we show that the TAK1 -> IKK beta -> 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.
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页数:10
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