Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10765508 | Biochemical and Biophysical Research Communications | 2010 | 5 Pages |
Abstract
In Cystic Fibrosis (CF), the absence of functional Cystic Fibrosis Transmembrane conductance Regulator (CFTR) translates into chronic bacterial infection, excessive inflammation, tissue damage, impaired lung function and eventual death. Understanding the mechanisms underlying this vicious circle of inflammation is key to better therapies for CF. In this manuscript, we have found that the presence of IL-17 in the airways of CF patients not only exacerbates inflammation through the recruitment of neutrophils via secretion of CXCL8, but also by priming airway epithelial cells lacking functional CFTR to increase response to the bacterial sensor NOD1. IL-17 stimulation of airway epithelial cells (AECs) lacking functional CFTR increased the expression of NOD1, NOD2, TLR4 and its own receptors IL-17RA and IL-17RC. Moreover, prior stimulation of AECs expressing the CFTRÎF508 mutant with IL-17 showed much greater CXCL8 secretion in response to a NOD1 agonist and Pseudomonas aeruginosa diffusible material. Taken together our results show that IL-17 primes AECs expressing CFTRÎF508 to increase host defence response to bacteria through the up-regulation of PRRs, and in particular of NOD1, and identifies another mechanism of action through which the CFTRÎF508 mutation leads to increase inflammation in response to bacterial ligands. Therefore preventing IL-17 function in CF may prove an important strategy in decreasing lung inflammation due to both direct and indirect effects.
Keywords
CFTRTAKCIKSTRAFCXCL8IRFNLRPRRAECsERKNODLPSqPCRMYD88CF transmembrane conductance regulatorMAPKNFκBTLRsinflammationinterleukinBacterianucleotide-binding oligomerization domainLungreal-time quantitative PCRAirway epithelial cellsIRAKnuclear factor κBinterferon response factorCystic fibrosisLipopolysaccharidesPAFSignal transductionRIPmitogen-activated protein kinaseReceptor-interacting proteinextracellular signal-regulated kinasepattern recognition receptorReceptorsNOD-like receptorsToll-like receptors
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Authors
Lucie Roussel, Simon Rousseau,