title: The protein kinases TPL2 and EGFR contribute to ERK1/ERK2 hyper-activation in CFTRΔF508-expressing airway epithelial cells exposed to Pseudomonas aeruginosa.
abstract: Excessive inflammation and Pseudomonas aeruginosa infection are two major characteristics of cystic fibrosis (CF) lung disease. In this manuscript, we describe a novel mechanism of ERK1/ERK2 activation and CXCL8 expression in AECs lacking functional CFTR. In both non-CF and CF airway epithelial cells (AECs), the protein kinase TPL2 is required for ERK1/ERK2 MAPK activation. However, we have found that EGFR is strongly phosphorylated in the airway epithelium of CF lung and contributes to ERK1/ERK2 MAPK activation in CF AECs exposed to P. aeruginosa diffusible material (PsaDM). Moreover, PsaDM stimulates the expression of the EGFR pro-ligand HB-EGF more strongly, and in a sustained manner, in CF AECs compared to non-CF cells. Finally, although both non-CF and CF AECs expresses CXCL8 in response to PsaDM, the levels of CXCL8 are higher and EGFR plays a more important role in regulating CXCL8 synthesis in CF AECs. Together, our finding shows that in addition to the TLR-mediated TPL2 activation of ERK1/ERK2, an additional pathway contributing to ERK1/ERK2 activation is triggered by infection of CF AECs: the EGFR signalling pathway. This second pathway may contribute to excessive inflammation observed in CF.
authors: Meakins-Christie Laboratories, McGill University Health Centre Research Institute, Montreal, Canada.
authors: Guy
authors: G
authors: Martel
authors: Meakins-Christie Laboratories, McGill University Health Centre Research Institute, Montreal, Canada.
authors: Lucie
authors: L
authors: Roussel
authors: Meakins-Christie Laboratories, McGill University Health Centre Research Institute, Montreal, Canada. Electronic address: sim.rousseau@mcgill.ca.
authors: Simon
authors: S
authors: Rousseau
keywords: AEC; CF; CF transmembrane regulator; CFTR; CXCL8; Cystic Fibrosis; EGF; EGF receptor; EGFR; ERK; Epidermal growth factor; Extracellular signal-Regulated Kinase; MAPK; Mitogen-Activated Protein Kinase; P. aeruginosa Diffusible Material; PsaDM; TLR; TPL2; Toll- like receptors; Toll-like receptors; Tumor Progression Locus 2; airway epithelial cells; cystic fibrosis; epidermal growth factor; mitogen activated protein kinase