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

Anta Ngkelo, Roland F. Hoffmann, Andrew L. Durham, John A. Marwick, Simone M. Brandenburg, Harold G. de Bruin, Marnix R. Jonker, Christos Rossios, Eleni Tsitsiou, Gaetano Caramori, Marco Contoli, Paolo Casolari, Francesco Monaco, Filippo Ando, Giuseppe Speciale, Iain Kilty, Kian F. Chung, Alberto Papi, Mark A. Lindsay, Nick H. T. ten HackenMaarten van den Berge, Wim Timens, Peter J. Barnes, Antoon J. van Oosterhout, Ian M. Adcock*, Paul A. Kirkham, Irene H. Heijink

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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/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.

Original languageEnglish
Pages (from-to)L1112-L1123
Number of pages12
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume309
Issue number10
DOIs
Publication statusPublished - 15-Nov-2015

Keywords

  • COPD
  • oxidative stress
  • inflammatory responses
  • monocytes
  • epithelial cells
  • OBSTRUCTIVE PULMONARY-DISEASE
  • PROINFLAMMATORY CYTOKINE RELEASE
  • ALVEOLAR EPITHELIAL-CELLS
  • CIGARETTE-SMOKE
  • HISTONE DEACETYLASE
  • OXIDATIVE STRESS
  • KAPPA-B
  • CORTICOSTEROID RESISTANCE
  • AIRWAY EPITHELIUM
  • PHOSPHORYLATION

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