Cilomilast counteracts the effects of cigarette smoke in innate immunity responses of airway epithelial cells

Airway epithelium is emerging as a regulator of innate immune responses to a variety of insults including cigarette smoke. Cigarette smoke extracts (CSE) increase the expression of TLR4 and alter its activation in bronchial epithelial cells. Cilomilast, a phosphodiesterase 4 inhibitor, inhibits cigarette smoke-induced neutrophilia. The main goal of this study was to explore whether cilomilast, in a human bronchial epithelial cell line (16-HBE), is able to counteract some of the effects of CSE. In particular, the expression of TLR4 (by flow-cytometry), the release of IP-10 and of IL-8 (by ELISA), the chemotactic activity toward lymphocytes and neutrophils (by microchemotaxis chamber) and the phosphorylation of ERK and of IkBa (by western blot analysis) in CSE and LPS-stimulated 16-HBE were assessed. In LPS-stimulated 16-HBE, CSE increased TLR4 expression, reduced both the IP-10 release and the chemotactic activity toward lymphocyte and increased both the IL-8 release and the chemotactic activity toward neutrophils. Cilomilast counteracted these effects due to CSE exposure reducing the expression of TLR4, increasing both the release of IP-10 and the chemotactic activity toward lymphocytes and toward neutrophils. No significant effect was observed on the release of IL-8. All these effects mediated by cilomilast are associated with a reduced ERK1/2 phosphorylation and with an increased IkBa phosphorylation. In conclusion, the results of the present study provide compelling evidences that cilomilast may be considered a possible valid therapeutic option in controlling inflammatory processes present in smokers