title: The protein kinase TPL2 is essential for ERK1/ERK2 activation and cytokine gene expression in airway epithelial cells exposed to pathogen-associated molecular patterns (PAMPs).
abstract: The epithelium forms a physical barrier important to the detection of pathogens. P. aeruginosa infections are frequently encountered in Cystic Fibrosis lungs, lead to ERK1/ERK2 activation and contribute to tissue destruction. We report here that in bronchial airway epithelial cells (BEAS-2B), diffusible material from P. aeruginosa and TLR2, TLR3 and TLR5 ligands activates ERK1/ERK2 via the protein kinase TPL2 and not the growth factor receptor EGFR. Activation of TPL2 by these agonists in airway epithelial cells requires the protein kinases TAK1 and IKKβ in accordance with the previously reported model of activation of TPL2 in macrophages. Inhibition of TPL2 activity with a pharmacological inhibitor (Compound 1) not only prevented ERK1/ERK2 activation but also decreased cytokine synthesis in response to pathogen-associated molecular patterns. These results suggest that inhibition of the protein kinase TPL2 is an attractive strategy to decrease inflammation in the lungs when it is not warranted.
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Martel
authors.forename: Julie
authors.initials: J
authors.lastname: Bérubé
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
mesh_terms: D002461:Cell Line, Transformed; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016207:Cytokines; D066246:ErbB Receptors; D051550:I-kappa B Kinase; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011518:Proto-Oncogene Proteins; D019908:Proto-Oncogene Proteins c-raf; D051193:Toll-Like Receptors; D000099151:MAP Kinase Kinase Kinase 7; C069937:MAP3K8 protein, human