학술논문
Glycogen synthase kinase-3[beta] modulation of glucocorticoid responsiveness in COPD. (CALL FOR PAPERS: Biomarkers in Lung Diseases: from Pathogenesis to Prediction to New Therapies)
Document Type
Author abstract
Author
Ngkelo, Anta; Hoffmann, Roland F.; Durham, Andrew L.; Marwick, John A.; Brandenburg, Simone M.; de Bruin, Harold G.; Jonker, Marnix R.; Rossios, Christos; Tsitsiou, Eleni; Caramori, Gaetano; Contoli, Marco; Casolari, Paolo; Monaco, Francesco; Ando, Filippo; Speciale, Giuseppe; Kilty, Iain; Chung, Kian F.; Papi, Alberto; Lindsay, Mark A.; ten Hacken, Nick H.T.; van den Berge, Maarten; Timens, Wim; Barnes, Peter J.; van Oosterhout, Antoon J.; Adcock, Ian M.; Kirkham, Paul A.; Heijink, Irene H.
Source
American Journal of Physiology (Consolidated). Nov, 2015, Vol. 309 Issue 5, pL1112, 12 p.
Subject
Language
English
ISSN
0002-9513
Abstract
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-3[beta] (GSK3[beta]) inactivation plays a key role in mediating signaling processes upon reactive oxygen species (ROS) exposure. We hypothesized that GSK3[beta] is involved in oxidative stress-induced glucocorticoid insensitivity in COPD. We studied levels of phospho-GSK3[beta]-Ser9, a marker of GSK3[beta] inactivation, in lung sections and cultured monocytes and bronchial epithelial cells of COPD patients, control smokers, and nonsmokers. We observed increased levels of phospho-GSK3[beta]-Ser9 in monocytes, alveolar macrophages, and bronchial epithelial cells from COPD patients and control smokers compared with nonsmokers. Pharmacological inactivation of GSK3[beta] did not affect CXCL8 or granulocytemacrophage 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 GSK3[beta] 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 GSK3[beta] inactivation. In conclusion, we demonstrate for the first time that ROS-induced glucocorticoid unresponsiveness in COPD is mediated through GSK3[beta], acting as a ROS-sensitive hub. COPD; oxidative stress; inflammatory responses; monocytes; epithelial cells doi: 10.1152/ajplung.00077.2015.