Glycogen synthase kinase-3β modulation of glucocorticoid responsiveness in COPD.
Anta NgkeloRoland F HoffmannAndrew L DurhamJohn A MarwickSimone M BrandenburgHarold G de BruinMarnix R JonkerChristos RossiosEleni TsitsiouGaetano CaramoriMarco ContoliPaolo CasolariFrancesco MonacoFilippo AndòGiuseppe SpecialeIain KiltyKian F ChungAlberto PapiMark A LindsayNick H T Ten HackenMaarten van den BergeWim TimensPeter J BarnesAntoon J van OosterhoutIan M AdcockPaul A KirkhamIrene H HeijinkPublished in: American journal of physiology. Lung cellular and molecular physiology (2015)
In chronic obstructive pulmonary disease (COPD), oxidative stress regulates the inflammatory response of bronchial epithelium and monocytes/macrophages through kinase modulation and has been linked to glucocorticoid unresponsiveness. Glycogen synthase-3β (GSK3β) inactivation plays a key role in mediating signaling processes upon reactive oxygen species (ROS) exposure. We hypothesized that GSK3β is involved in oxidative stress-induced glucocorticoid insensitivity in COPD. We studied levels of phospho-GSK3β-Ser9, a marker of GSK3β inactivation, in lung sections and cultured monocytes and bronchial epithelial cells of COPD patients, control smokers, and nonsmokers. We observed increased levels of phospho-GSK3β-Ser9 in monocytes, alveolar macrophages, and bronchial epithelial cells from COPD patients and control smokers compared with nonsmokers. Pharmacological inactivation of GSK3β did not affect CXCL8 or granulocyte-macrophage colony-stimulating factor (GM-CSF) expression but resulted in glucocorticoid insensitivity in vitro in both inflammatory and structural cells. Further mechanistic studies in monocyte and bronchial epithelial cell lines showed that GSK3β inactivation is a common effector of oxidative stress-induced activation of the MEK/ERK-1/2 and phosphatidylinositol 3-kinase/Akt signaling pathways leading to glucocorticoid unresponsiveness. In primary monocytes, the mechanism involved modulation of histone deacetylase 2 (HDAC2) activity in response to GSK3β inactivation. In conclusion, we demonstrate for the first time that ROS-induced glucocorticoid unresponsiveness in COPD is mediated through GSK3β, acting as a ROS-sensitive hub.
Keyphrases
- signaling pathway
- pi k akt
- chronic obstructive pulmonary disease
- induced apoptosis
- cell cycle arrest
- reactive oxygen species
- lung function
- cell proliferation
- dendritic cells
- oxidative stress
- inflammatory response
- end stage renal disease
- histone deacetylase
- peripheral blood
- dna damage
- epithelial mesenchymal transition
- ejection fraction
- newly diagnosed
- prognostic factors
- cell death
- adipose tissue
- tyrosine kinase
- poor prognosis
- cystic fibrosis
- cerebrospinal fluid
- long non coding rna
- patient reported