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

Kittipong Maneechotesuwan,Adisak Wongkajornsilp,Kanda Kasetsinsombat,Peter J Barnes

doi:10.1186/s12931-016-0424-6

Kittipong Maneechotesuwan, Adisak Wongkajornsilp + Show 2 more

Open Access

https://doi.org/10.1186/s12931-016-0424-6

Copy DOI

Abstract

BackgroundAdenosine 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.MethodsWe 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.ResultsSimvastatin 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.ConclusionSimvastatin 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0424-6) contains supplementary material, which is available to authorized users.

Highlights

Adenosine deaminase (ADA) and osteopontin (OPN) may play opposing roles in the pathogenesis of Chronic obstructive pulmonary disease (COPD)
Because IL-13 is induced by adenosine and induces OPN expression [18, 30, 31], we investigated whether simvastatin suppresses IL-13 production in the airways of COPD patients
We have demonstrated for the first time that simvastatin enhances adenosine deaminase (ADA) expression while inhibiting osteopontin via inhibition of STAT6-dependent IL-13 signaling

Summary

Introduction

Adenosine deaminase (ADA) and osteopontin (OPN) may play opposing roles in the pathogenesis of COPD. Adenosine plays a key role in airway inflammation and remodeling in COPD [4]. Extracellular adenosine was produced upon cell damage to balance tissue repair against excessive airway remodeling in COPD [5,6,7,8,9,10]. CD73 expression and activity is markedly increased in patients with severe COPD, suggesting the high production of adenosine [3]. The synergistic effect of adenosine and IL-13 may contribute to the severity of airway inflammation and fibrosis in COPD [14]. Suppression of ADA activity together with CD73 upregulation promotes adenosine production in the COPD lungs [3]. The pathological features of COPD was prevented and reversed by lowering adenosine levels with exogenous PEG-ADA [14,15,16,17]

Methods

Results

Discussion

Conclusion