Proinflammatory signal transduction in epithelial cells: the model of cystic fibrosis lung disease

Cystic Fibrosis (CF) is a severe inherited disease caused by mutations of the gene encoding for a chloride channel termed CFTR. Albeit CF is a multiple-organ disease, lung inflammation is the most common cause of morbidity and mortality. CF lung pathology is characterized by huge infiltrates of neutrophils (PMNs) into the lung lumen and by excessive release of cytokines and chemokines, in particular IL-8. After bacterial infection, sustained mainly by P.aeruginosa, this inflammatory process is amplified, leading to massive recruitment of PMNs which contributes to lung tissue damage. Our goal is gain further insights into the pro-inflammatory signal transduction that underlies the CF lung inflammation. Here we reported that P.aeruginosa-dependent transmembrane signalling pathway in bronchial epithelia occurs on the one hand via Toll Like Receptors (TLRs) activation, thus by activation of MAPK p38, ERK-1/2, JNK and their downstream effectors HSP27, RSK and IKK; on the other hand via ATP release and purinergic activation which in turn activates Phospholipase-C beta (PLCB). This enzyme is able to induce intracellular calcium signalling, triggering the PKC activation. Furthermore, here we reported that many of the kinases involved are able to promote activation of several Transcription Factors (TFs), such as CREB, CHOP, AP-1, NF-IL6 and NF-kB. These TFs bind to the proximal promoter region of IL-8 gene causing its expression. Moreover, results indicate that PLCB1, PLCB3 and PLCB4 isoforms seem to be redundantly activated by P.aeruginosa-dependent ATP release through purinergic receptor binding. Concluding, the final aim of this PhD program is deepen the pro-inflammatory transmembrane signalling to provide a panel of molecular targets in order to support the future development of novel therapies for CF lung inflammation.