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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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