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

Date Published: August 1, 2017

Publisher: American Physiological Society

Author(s): Satoru Yanagisawa, Jonathan R. Baker, Chaitanya Vuppusetty, Peter Fenwick, Louise E. Donnelly, Kazuhiro Ito, Peter J. Barnes.


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 of l-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.

Partial Text

In the current study, we have shown for the first time that the PTEN protein levels were significantly decreased in the peripheral lung of patients with COPD. PTEN protein levels were positively correlated with the severity of air flow obstruction and showed a strong negative correlation with the Akt phosphorylation, indicating activation of the PI3K signaling pathway. This is consistent with the modulatory role of PTEN on PI3K signaling (41).

This project was supported by the Wellcome Trust Programme Grant 093080/Z/10/Z. S. Yanagisawa is a recipient of a Banyu Life Science Foundation International fellowship. P. J. Barnes and C. Vuppusetty are recipients of Wellcome Trust Grant 093080/Z/10/Z.

P. J. Barnes has served on Scientific Advisory Boards of AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Johnson & Johnson, Napp, Novartis, Takeda, Pfizer, Prosonix, RespiVert, Teva, and Zambon and has received research funding from AstraZeneca, Boehringer-Ingelheim, Chiesi, Novartis, and Takeda. K. Ito is currently an employee of Pulmocide, Ltd., and has honorary contract with Imperial College.

P.J.B. conceived and designed research. S.Y., J.R.B., C.V., and P.F. performed experiments; S.Y., J.R.B., and C.V. analyzed data; S.Y., J.R.B., C.V., L.E.D., K.I., and P.J.B. interpreted results of experiments; S.Y., J.R.B., C.V., and K.I. prepared figures; S.Y., K.I., and P.J.B. drafted manuscript; S.Y., K.I., and P.J.B. edited and revised manuscript; S.Y., K.I., and P.J.B. approved final version of manuscript.




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