title: Aberrantly activated EGFR contributes to enhanced IL-8 expression in COPD airways epithelial cells via regulation of nuclear FoxO3A.
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.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109-5688, USA.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Ganesan
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Unger
authors.forename: Adam T
authors.initials: AT
authors.lastname: Comstock
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Angel
authors.forename: Peter
authors.initials: P
authors.lastname: Mancuso
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.forename: Umadevi S
authors.initials: US
authors.lastname: Sajjan
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000737:chemistry; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D011794:Quercetin / Q000008:administration & dosage / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D016209:Interleukin-8; D011794:Quercetin; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt