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Original article
Aberrantly activated EGFR contributes to enhanced IL-8 expression in COPD airways epithelial cells via regulation of nuclear FoxO3A
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  1. Shyamala Ganesan1,
  2. Benjamin L Unger1,
  3. Adam T Comstock1,
  4. Kristen A Angel2,
  5. Peter Mancuso2,
  6. Fernando J Martinez3,
  7. Umadevi S Sajjan1
  1. 1Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA
  2. 2Department of Environmental Health Science, University of Michigan, Ann Arbor, Michigan, USA
  3. 3Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Professor Umadevi S Sajjan, Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5688, USA; usajjan{at}umich.edu

Abstract

Background Decreased activity of forkhead transcription factor class O (FoxO)3A, a negative regulator of NF-κB-mediated chemokine expression, is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Previously, we showed that quercetin reduces lung inflammation in a murine model of COPD. Here, we examined the mechanisms underlying decreased FoxO3A activation and its modulation by quercetin in COPD human airway epithelial cells and in a COPD mouse model.

Methods Primary COPD and normal human airway epithelial cells were treated with quercetin, LY294002 or erlotinib for 2 weeks. IL-8 was measured by ELISA. FoxO3A, Akt, and epidermal growth factor (EGF) receptor (EGFR) phosphorylation and nuclear FoxO3A levels were determined by Western blot analysis. Effects of quercetin on lung chemokine expression, nuclear FoxO3A levels and phosphorylation of EGFR and Akt were determined in COPD mouse model.

Results Compared with normal, COPD cells showed significantly increased IL-8, which negatively correlated with nuclear FoxO3A levels. COPD bronchial biopsies also showed reduced nuclear FoxO3A. Decreased FoxO3A in COPD cells was associated with increased phosphorylation of EGFR, Akt and FoxO3A and treatment with quercetin, LY294002 or erlotinib increased nuclear FoxO3A and decreased IL-8 and phosphorylation of Akt, EGFR and FoxO3A, Compared with control, elastase/LPS-exposed mice showed decreased nuclear FoxO3A, increased chemokines and phosphorylation of EGFR and Akt. Treatment with quercetin partially reversed these changes.

Conclusions In COPD airways, aberrant EGFR activity increases PI 3-kinase/Akt-mediated phosphorylation of FoxO3A, thereby decreasing nuclear FoxO3A and increasing chemokine expression. Quercetin restores nuclear FoxO3A and reduces chemokine expression partly by modulating EGFR/PI 3-kinase/Akt activity.

  • Airway Epithelium
  • COPD Mechanisms
  • Oxidative Stress
  • Cytokine Biology
  • Complementary Medicine
  • COPD Pathology
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