Decreased phosphatase PTEN amplifies PI3K signaling and enhances proinflammatory cytokine release in COPD

Satoru Yanagisawa, Jonathan R. Baker, Chaitanya Vuppusetty, Peter Fenwick, Louise E. Donnelly, Kazuhiro Ito, Peter J. Barnes

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. The aim of this study was to determine the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in COPD. PTEN protein expression was measured in the peripheral lung of COPD patients compared with smoking and nonsmoking controls. The direct influence of cigarette smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence ofL-buthionine-sulfoximine (BSO) to deplete intracellular glutathione. The impact of PTEN knockdown by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared with the subjects without COPD (P < 0.001) and positively correlated with the severity of airflow obstruction (forced expiratory volume in 1-s percent predicted; r = 0.50; P = 0.0012). Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels (r =-0.41; P = 0.0042). In both primary bronchial epithelial cells and BEAS-2B cells, CSE decreased PTEN protein, which was reversed by N-acetyl cysteine treatment. PTEN knockdown potentiated Akt phosphorylation and enhanced production of proinflammatory cytokines, such as IL-6, CXCL8, CCL2, and CCL5. In conclusion, oxidative stress reduces PTEN protein levels, which may result in increased PI3K signaling and amplification of inflammation in COPD.

Original languageEnglish
Pages (from-to)L230-L239
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume313
Issue number2
DOIs
Publication statusPublished - 2017

Keywords

  • Chronic obstructive pulmonary disease
  • Oxidative stress
  • PI3K IL-6
  • Phosphatase and tensin homolog deleted from chromosome 10

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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