Combination of erythromycin and dexamethasone improves corticosteroid sensitivity induced by CSE through inhibiting PI3K-δ/Akt pathway and increasing GR expression

Xue-Jiao Sun, Zhan-Hua Li, Yang Zhang, Guang Zhou, Jian-Quan Zhang, Jing-Min Deng, Jing Bai, Guang-Nan Liu, Mei-Hua Li, William MacNee, Xiao-Ning Zhong, Zhi-Yi He

Research output: Contribution to journalArticlepeer-review

Abstract

Corticosteroid insensitivity, which is induced by cigarette smoke extract (CSE), is a significant barrier when treating chronic obstructive pulmonary disease (COPD). Erythromycin (EM) has been shown to have an anti-inflammatory role in some chronic airway inflammatory diseases, particularly diffuse panbronchiolitis and cystic fibrosis. Here, we explored whether the combination therapy of EM and dexamethasone (Dex) reverses corticosteroid insensitivity and investigated the molecular mechanism by which this occurs. We demonstrated that the combination of EM and Dex restored corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from COPD patients and U937 cells after CSE exposure. Moreover, pretreatment with 10, 50, or 100 μg/ml EM reversed the HDAC2 protein reduction induced by CSE exposure in a dose-dependent manner. U937 cells exposed to CSE show a reduction in histone deacetylase (HDAC) activity, which was potently reversed by EM or combination treatment. Although 10 and 17.5% CSE increased phosphorylated Akt (PAkt) expression in a concentration-dependent manner, preapplication of EM and the combination treatment in particular blocked this PAkt increase. Total Akt levels were unaffected by CSE or EM treatments. Furthermore, the combination treatment enhanced glucocorticoid receptor (GR)α expression. Our results demonstrate that the combination therapy of EM and Dex can restore corticosteroid sensitivity through inhibition of the PI3K-δ/Akt pathway and enhancing GRα expression.

Original languageEnglish
Pages (from-to)L139-46
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume309
Issue number2
DOIs
Publication statusPublished - 15 Jul 2015

Keywords

  • Adrenal Cortex Hormones
  • Anti-Inflammatory Agents
  • Blotting, Western
  • Case-Control Studies
  • Dexamethasone
  • Drug Therapy, Combination
  • Erythromycin
  • Gastrointestinal Agents
  • Histone Deacetylase 2
  • Humans
  • Interleukin-8
  • Leukocytes, Mononuclear
  • Oxidative Stress
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Pulmonary Disease, Chronic Obstructive
  • Receptors, Glucocorticoid
  • Smoking
  • U937 Cells

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