br Introduction Chronic rhinosinusitis with nasal

Introduction Chronic rhinosinusitis with nasal polyps (CRSwNP), a subgroup of chronic rhinosinusitis (CRS), is a chronic inflammatory condition of the nasal and paranasal sinuses. CRSwNP is characterized by grape-like structures with dense inflammatory infiltrates, loose fibrous choline fenofibrate and thickened basement membrane in the upper nasal cavity, with a prevalence about 1–4% of the general population (Fokkens et al., 2012, Hastan et al., 2011). The major phenotypic markers of CRSwNP are a predominately eosinophilic cellular infiltration and eosinophilic Th2 inflammation while the inflammatory process is characterized by interleukin (IL)-4, IL-5, eosinophil cationic protein (ECP) and eotaxin-1/-2/-3 expression (Fokkens et al., 2012, Plager et al., 2010, Van Zele et al., 2006). The Wnt/β-catenin signaling pathway is involved in the regulation of various cellular functions throughout development and adult life of all animals (Clevers and Nusse, 2012). There is evidence that the Wnt signaling pathway is essential for development, differentiation and function of the airway (Mucenski et al., 2005, Mucenski et al., 2003, Okubo and Hogan, 2004), additionally this pathway has been linked to the pathogenesis of different diseases, like chronic lung disease (Konigshoff and Eickelberg, 2010). β-catenin plays a key role in the Wnt signaling output and influences gene transcription in several ways. The APC/Axin/GSK-3-complex triggers the coordinated phosphorylation of β-catenin, leading to its ubiquitination and proteasomal degradation through the β-TrCP/SKP pathway (Clevers and Nusse, 2012). Once β-catenin phosphorylation is inhibited, its degradation decreased and undergoes nuclear translocation, called active β-catenin. Within the nucleus, ß-catenin regulates gene expression via T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, which are multifunctional proteins that use their sequence-specific DNA-binding and context-dependent interactions to specify which genes will be regulated by Wnts (Cadigan and Waterman, 2012, Logan and Nusse, 2004, Moon et al., 2004). GSK-3 is involved in the regulation of various biosynthetic pathways and various kinases are able to regulate the GSK-3 activity via phosphorylation at its activating or inhibiting phosphorylation sites. Several recent studies suggest an active role of glycogen synthase kinase 3 (GSK-3) in several diseases such as Alzheimer's disease, cancer, inflammation, cardiovascular disease, or diabetes. There are two different GSK-3 isoforms known, namely GSK-3α and GSK-3β, which are encoded by 2 different genes. GSK-3 activity itself has been shown to be regulated by different phosphorylation patterns. While the phosphorylation of serine-9 in GSK-3α or serine-21 in GSK-3β leads to a decreased enzyme activity, a strongly increased enzymatic activity can be detected in response to the phosphorylation of residues tyrosine-279 in GSK-3α and tyrosine-216 in GSK-3β (Kaidanovich-Beilin and Woodgett, 2011). Unlike other kinases the enzyme is constitutively active and is inactivated in response to cellular signals. Akt-kinase (also known as PKB) was identified as an oncogene with serine/threonine kinase activity and was shown to be a negative regulator of GSK-3-β activity in vivo. Akt can be activated via phosphorylation at Ser473 by PDK1, whereas it has been suggested that PHLPP may function as an inhibitor of this phosphorylation (Gao et al., 2005). The natural monoterpene and major compound of many plant essential oils 1,8-cineol, also known as eucalyptol, has proven clinical efficacy on the respiratory tract and has shown therapeutic benefits in inflammatory airway diseases, such as asthma or chronic obstructive pulmonary disease (COPD). Several pre-clinical studies refers to its anti-inflammatory and anti-oxidant mode of action with strong evidence that 1,8-cineol controls inter alia inflammatory processes, but its effect on the pathogenesis of nasal polyps is still not understood (Juergens, 2014).