期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 309, 期 10, 页码 L1112-L1123出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00077.2015
关键词
COPD; oxidative stress; inflammatory responses; monocytes; epithelial cells
资金
- Top Institute Pharma Project COPD, Transition of Systemic Inflammation into Multi-Organ Pathology [T1-201]
- National Institute for Health Research Respiratory Biomedical Research Unit at the Royal Brompton
- Harefield National Health Service Foundation
- Imperial College London
- Biotechnology and Biological Sciences Research Council CASE award
- Pfizer
- Wellcome Trust programme grant
- COPD-MAP
- AstraZeneca Italy
- Boehringer Ingelheim Italy
- GSK Italy
- Menarini
- National Institute for Health Research [NF-SI-0611-10148] Funding Source: researchfish
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/ERK1/2 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.
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