Glycogen synthase kinase-3β modulation of glucocorticoid responsiveness in COPD

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-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.

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…Inactivated GSK3b (p-GSKb-Ser 9 ) is increased in PBMC, macrophages, and airway epithelial cells of patients with COPD, especially those with severe disease (Ngkelo et al, 2015). This is associated with corticosteroid resistance as a result of reduced HDAC2 in these cells, which is mimicked by GSK3b knockdown and a GSK3b inhibitor CT99021 [6-[[2-[[4-(2,4-…”

Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy

“…They further showed reduced recruitment of the GR to the GILZ promoter. Pharmacological inhibition of GSK3β impairs the ability of GCs to repress lipopolysaccharide (LPS)-induction of pro-inflammatory cytokines in primary bronchial epithelial cells and monocytes (Ngkelo et al, 2015). Individuals with COPD show resistance to GCs and using tissue biopsies from a cohort of COPD patients, Ngkelo et al demonstrated that GSK3β is hyperphosphorylated in these samples.…”

<p>Dual Role For A MEK Inhibitor As A Modulator Of Inflammation And Host Defense Mechanisms With Potential Therapeutic Application In COPD</p>

“…Furthermore, increased inactivation of glycogen synthase-3β (GSK-3 β) was reported in COPD patients, that is thought to play a key role in oxidative stress and subsequent steroid insensitivity. 15 This inactivation was mechanistically linked to activation of the MEK/ERK pathway and the phosphatidylinositol 3-kinase/AKT pathways in epithelial and immune cells. 15 In addition, Rhinovirus (RV), a respiratory virus that causes COPD exacerbations, induces the expression of IL-8/CXCL8 in a MEK-dependent manner.…”

“…15 This inactivation was mechanistically linked to activation of the MEK/ERK pathway and the phosphatidylinositol 3-kinase/AKT pathways in epithelial and immune cells. 15 In addition, Rhinovirus (RV), a respiratory virus that causes COPD exacerbations, induces the expression of IL-8/CXCL8 in a MEK-dependent manner. 16 However, a more direct association between MEK pathway activation and COPD is yet to be established.…”