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Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism.

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Title: Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism.
Authors: Maneechotesuwan, K
Kasetsinsombat, K
Wongkajornsilp, A
Barnes, PJ
Item Type: Journal Article
Abstract: BACKGROUND: Adenosine deaminase (ADA) and osteopontin (OPN) may play opposing roles in the pathogenesis of COPD. Deficiency of ADA results in enhanced adenosine signaling which up-regulates OPN expression. Although statins suppress OPN in cancer cells, little is known about their effects on ADA and OPN in COPD patients. METHODS: We extended a previous randomized double-blind placebo crossover study to investigate the effects of simvastatin (20 mg/day) on sputum ADA and OPN expression and explored the underlying signaling pathways involved by conducting in vitro experiments with cigarette smoke extract (CSE)-treated monocyte-derived macrophages (MDM) from COPD patients and healthy subjects. RESULTS: Simvastatin decreased sputum IL-13, OPN and CD73, while increasing ADA expression, irrespective of inhaled corticosteroid treatment and smoking status in parallel to increased inosine levels. The degree of simvastatin-restored ADA activity was significantly correlated with the magnitude of changes in pre-bronchodilator FEV1. Mechanistic exploration showed that CSE enhanced the expression of IL-13, which induced an increase in OPN and inhibited ADA mRNA accumulation in MDM from COPD patients but not healthy subjects through a STAT6-dependent mechanism. Simvastatin treatment inhibited IL-13 transcription in a dose-dependent manner, and therefore diminished the IL-13-induced increase in OPN and restored IL-13-suppressed ADA. There was no effect of simvastatin on adenosine receptors in CSE-stimulated MDM, indicating that its effects were on the adenosine pathway. CONCLUSION: Simvastatin reversed IL-13-suppressed ADA activity that leads to the down-regulation of adenosine signaling and therefore inhibits OPN expression through the direct inhibition of IL-13-activated STAT6 pathway. Inhibition of IL-13 may reverse the imbalance between ADA and OPN in COPD and therefore may prevent COPD progression.
Issue Date: 24-Aug-2016
Date of Acceptance: 20-Aug-2016
URI: http://hdl.handle.net/10044/1/39703
DOI: https://dx.doi.org/10.1186/s12931-016-0424-6
ISSN: 1465-993X
Publisher: BioMed Central
Journal / Book Title: Respiratory Research
Volume: 17
Issue: 1
Copyright Statement: © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: Pfizer Incorporated
Funder's Grant Number: 7C3-N-3019575
Keywords: Adenosine deaminase
COPD
IL-13
Osteopontin
Simvastatin
Respiratory System
1102 Cardiovascular Medicine And Haematology
1103 Clinical Sciences
Publication Status: Published
Article Number: 104
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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