Biomarkers in Lung Diseases: from Pathogenesis to Prediction to New Therapies Glycogen synthase kinase-3 modulation of glucocorticoid responsiveness in COPD

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.

[1]  B. Bettler,et al.  Lack of GABAB receptors modifies behavioural and biochemical alterations induced by precipitated nicotine withdrawal , 2015, Neuropharmacology.

[2]  Sung-joon Min,et al.  Neuroendocrine Signaling Via the Serotonin Transporter Regulates Clearance of Apoptotic Cells* , 2014, The Journal of Biological Chemistry.

[3]  I. Rahman,et al.  Serotonin and Corticosterone Rhythms in Mice Exposed to Cigarette Smoke and in Patients with COPD: Implication for COPD-Associated Neuropathogenesis , 2014, PloS one.

[4]  D. Postma,et al.  Oxidant-induced corticosteroid unresponsiveness in human bronchial epithelial cells , 2013, Thorax.

[5]  P. Barnes.  Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. , 2013, The Journal of allergy and clinical immunology.

[6]  M. Bacchetta,et al.  Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone. , 2013, American journal of physiology. Lung cellular and molecular physiology.

[7]  J. Riley,et al.  Targeted metabolomics identifies perturbations in amino acid metabolism that sub-classify patients with COPD. , 2012, Molecular bioSystems.

[8]  K. Chung,et al.  Restoration of Corticosteroid Sensitivity by p38 Mitogen Activated Protein Kinase Inhibition in Peripheral Blood Mononuclear Cells from Severe Asthma , 2012, PloS one.

[9]  Weiliang Qiu,et al.  Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome. , 2012, Human molecular genetics.

[10]  Byung-Hoon Lee,et al.  Proteasome inhibition-induced p38 MAPK/ERK signaling regulates autophagy and apoptosis through the dual phosphorylation of glycogen synthase kinase 3β. , 2012, Biochemical and biophysical research communications.

[11]  K. Sladek,et al.  Thrombin generation in chronic obstructive pulmonary disease: dependence on plasma factor composition. , 2011, Thrombosis research.

[12]  P. Cooper,et al.  C-027 inhibits IgE-mediated passive sensitization bronchoconstriction and acts as a histamine and serotonin antagonist in human airways. , 2011, Allergy and asthma proceedings.

[13]  D. Postma,et al.  Role of aberrant metalloproteinase activity in the pro-inflammatory phenotype of bronchial epithelium in COPD , 2011, Respiratory research.

[14]  D. Postma,et al.  Cigarette smoke impairs airway epithelial barrier function and cell–cell contact recovery , 2011, European Respiratory Journal.

[15]  F. Wandosell,et al.  Deconstructing GSK-3: The Fine Regulation of Its Activity , 2011, International journal of Alzheimer's disease.

[16]  E. Spindel,et al.  Prenatal nicotine exposure increases GABA signaling and mucin expression in airway epithelium. , 2011, American journal of respiratory cell and molecular biology.

[17]  J. Marwick,et al.  Molecular mechanisms of oxidative stress in airways and lungs with reference to asthma and chronic obstructive pulmonary disease , 2010, Annals of the New York Academy of Sciences.

[18]  Ronit Vogt Sionov,et al.  Glycogen synthase kinase-3 plays a central role in mediating glucocorticoid-induced apoptosis. , 2010, Molecular endocrinology.

[19]  I. Adcock,et al.  A role for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease. , 2010, The Journal of allergy and clinical immunology.

[20]  D. Postma,et al.  House dust mite-promoted epithelial-to-mesenchymal transition in human bronchial epithelium. , 2010, American journal of respiratory cell and molecular biology.

[21]  D. Slebos,et al.  Lipid-soluble components in cigarette smoke induce mitochondrial production of reactive oxygen species in lung epithelial cells. , 2009, American journal of physiology. Lung cellular and molecular physiology.

[22]  I. Adcock,et al.  Glucocorticoid resistance in inflammatory diseases , 2009, The Lancet.

[23]  Hongwei Yao,et al.  Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke. , 2009, American journal of respiratory cell and molecular biology.

[24]  P. Chakravarty,et al.  Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. , 2008, American journal of respiratory cell and molecular biology.

[25]  D. Billadeau.  Primers on Molecular Pathways , 2007, Pancreatology.

[26]  D. Billadeau.  Primers on molecular pathways. The glycogen synthase kinase-3beta. , 2007, Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.].

[27]  R. Jope,et al.  Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics , 2007, Neurochemical Research.

[28]  I. Rahman,et al.  Differential effects of cigarette smoke on oxidative stress and proinflammatory cytokine release in primary human airway epithelial cells and in a variety of transformed alveolar epithelial cells , 2006, Respiratory research.

[29]  I. Rahman,et al.  Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. , 2006, Pharmacology & therapeutics.

[30]  I. Rahman.  Antioxidant therapies in COPD , 2006, International journal of chronic obstructive pulmonary disease.

[31]  I. Adcock,et al.  Alteration of adenosine receptors in patients with chronic obstructive pulmonary disease. , 2006, American journal of respiratory and critical care medicine.

[32]  I. Adcock,et al.  Histone deacetylase 2–mediated deacetylation of the glucocorticoid receptor enables NF-κB suppression , 2006, The Journal of experimental medicine.

[33]  I. Adcock,et al.  Decreased histone deacetylase activity in chronic obstructive pulmonary disease. , 2005, The New England journal of medicine.

[34]  I. Rahman,et al.  Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF‐κB activation and proinflammatory cytokine release in alveolar epithelial cells , 2004 .

[35]  Klaus Resch,et al.  Phosphorylation of Serine 468 by GSK-3β Negatively Regulates Basal p65 NF-κB Activity* , 2004, Journal of Biological Chemistry.

[36]  Irfan Rahman,et al.  Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. , 2004, American journal of respiratory cell and molecular biology.

[37]  I. Adcock,et al.  Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase , 2004, The Lancet.

[38]  I. Rahman,et al.  Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  Klaus Resch,et al.  Phosphorylation of serine 468 by GSK-3beta negatively regulates basal p65 NF-kappaB activity. , 2004, The Journal of biological chemistry.

[40]  B. Doble,et al.  GSK-3: tricks of the trade for a multi-tasking kinase , 2003, Journal of Cell Science.

[41]  L. Fabbri,et al.  Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. , 2003, Thorax.

[42]  K. Chung,et al.  Effect of acute and chronic inflammatory stimuli on expression of protease-activated receptors 1 and 2 in alveolar macrophages. , 2003, The Journal of allergy and clinical immunology.

[43]  H. Eldar-Finkelman,et al.  The role of glycogen synthase kinase-3 in insulin resistance and Type 2 diabetes , 2002, Expert opinion on therapeutic targets.

[44]  J. Davie,et al.  The Transcriptional Repressor Sp3 Is Associated with CK2-phosphorylated Histone Deacetylase 2* , 2002, The Journal of Biological Chemistry.

[45]  I. Adcock,et al.  Increased expression of nuclear factor-κB in bronchial biopsies from smokers and patients with COPD , 2002, European Respiratory Journal.

[46]  R. Jope,et al.  CREB DNA binding activity is inhibited by glycogen synthase kinase‐3β and facilitated by lithium , 2001, Journal of neurochemistry.

[47]  I. Adcock,et al.  Glucocorticoid Receptor Recruitment of Histone Deacetylase 2 Inhibits Interleukin-1β-Induced Histone H4 Acetylation on Lysines 8 and 12 , 2000, Molecular and Cellular Biology.

[48]  J. Woodgett,et al.  Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. , 1994, The Biochemical journal.