Publication: Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism
Issued Date
2016
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eng
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Mahidol University
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BioMed Central
Bibliographic Citation
Respiratory Research. Vol. 17, (2016), 104
Suggested Citation
Kittipong Maneechotesuwan, Kanda Kasetsinsombat, Adisak Wongkajornsilp, Barnes, Peter J. Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism. Respiratory Research. Vol. 17, (2016), 104. doi:10.1186/s12931-016-0424-6 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/2682
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Title
Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism
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.