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

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Title: Decreased phosphatase PTEN amplifies PI3K signaling and enhances pro-inflammatory cytokine release in COPD
Authors: Yanagisawa, S
Baker, JR
Vuppusetty, C
Fenwick, P
Donnelly, LE
Ito, K
Barnes, PJ
Item Type: Journal Article
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. Our aim 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 expression and activity were measured in the peripheral lung of COPD patients compared to smoking and non-smoking 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 knock-down by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared to the subjects without COPD (p < 0.001), and positively correlated with the severity of air-flow obstruction (FEV1 % predicted; r = 0.50; p = 0.0012), 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 = -0.41; p = 0.0042). Both in primary bronchial epithelial cells and BEAS-2B cell line, CSE decreased PTEN protein, which was reversed by N-acetylcysteine treatment. PTEN knock-down potentiated Akt phosphorylation and enhanced production of pro-inflammatory 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.
Issue Date: 18-May-2017
Date of Acceptance: 5-May-2017
URI: http://hdl.handle.net/10044/1/48446
DOI: https://dx.doi.org/10.1152/ajplung.00382.2016
ISSN: 1522-1504
Publisher: American Physiological Society
Start Page: L230
End Page: L239
Journal / Book Title: American Journal of Physiology-Lung Cellular and Molecular Physiology
Volume: 313
Issue: 2
Copyright Statement: Copyright © 2017 the American Physiological Society Licensed under Creative Commons Attribution CC-BY 4.0: © the American Physiological Society
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 093080/Z/10/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Physiology
Respiratory System
chronic obstructive pulmonary disease
phosphatase and tensin homolog deleted from chromosome 10
PI3K IL-6
oxidative stress
OBSTRUCTIVE PULMONARY-DISEASE
TUMOR-SUPPRESSOR PTEN
HUMAN LUNG CANCERS
REDOX REGULATION
EPITHELIAL-CELLS
NEGATIVE REGULATION
TENSIN HOMOLOG
INDUCED SPUTUM
GLUTATHIONE
INACTIVATION
Aged
Cell Line
Cytokines
Epithelial Cells
Female
Humans
Inflammation
Lung
Male
Oxidative Stress
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases
Phosphorylation
Proto-Oncogene Proteins c-akt
Pulmonary Disease, Chronic Obstructive
Signal Transduction
Smoke
Smoking
COPD
IL-6
PI3K
PTEN
0606 Physiology
1116 Medical Physiology
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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