Decreased PTEN amplifies PI3K signaling and enhances pro-inflammatory cytokine release in COPD

<b>Introduction and background:</b> The phosphatidylinositol-3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the mechanisms that regulate this pathway are yet to be elucidated. <b>Aims and objectives:</b> We investigated the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), the major negative regulator of the PI3K pathway in COPD. <b>Methods:</b> The protein levels and immunopurified PTEN activities were measured in peripheral lung from patients with COPD and compared to controls. Airways epithelial BEAS-2B cells were incubated with cigarette smoke extract (CSE) in the presence or absence of L-buthionine-sulfoximine (BSO), and the effect of PTEN knock–down by RNA interference was also examined. <b>Results:</b> PTEN protein was significantly decreased in peripheral lung of patients with COPD compared to the subjects without COPD (PTEN/β-actin ratio in healthy: 1.30±0.62 <i>vs</i> COPD: 0.71±0.27; p&lt;0.001), and positively correlated with the severity of airflow obstruction (FEV₁ %predicted; r=0.41; p=0.014), although no difference was observed in PTEN activity. Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels (r=-0.43; p=0.0085). In BEAS-2B cells, CSE decreased PTEN protein, mainly through the suppression of the mRNA transcription. PTEN knock-down potentiated Akt phosphorylation and enhanced production of pro-inflammatory cytokines, such as interleukin-6, and CXCL8. <b>Conclusions:</b> Oxidative stress reduces PTEN protein levels, which may result in increased PI3K signalling and amplification of inflammation in COPD.