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

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.

IRF4 and STAT3 activities are associated with the imbalanced differentiation of T-cells in responses to inhalable particulate matters

“…STAT3 activate Th17 upon IL-6 and IL-23R signaling and degrade by ubiquitination [60][61][62]. STAT3 is a known effector of PM [63][64][65]; IRF4 is also known for its function in Asthma by activating Th17 through regulation of chromatin accessibility but not for the role in response to PM exposure [66,67]. Together our data suggest a potential risk of PM exposure to allergic respiratory diseases and regulators of Th17/Treg imbalance are likely effectors of PM.…”

Association of the IL-13 polymorphisms rs1800925 and rs20541 with chronic obstructive pulmonary disease risk

“…[ 21 ] In addition, IL-13 enhanced monocyte-derived macrophages’ expression of osteopontin, a phosphorylated acidic glycoprotein that correlated with the degree of airflow limitation in smokers. [ 22 ] In vivo studies showed that the overexpression of IL-13 in the adult murine lung caused a phenotype that mirrored human COPD with prominent emphysema. [ 4 ] These lines of evidence suggested that IL-13 was implicated in the pathogenesis of COPD and genetic variations in the IL-13 gene may modify the risk for developing COPD.…”

Osteopontin as a Link between Inflammation and Cancer: The Thorax in the Spotlight

“…Although it is known that statins suppress OPN in cancer cells, their function in COPD was recently studied. Particularly, simvastatin was found to initiate downregulation of adenosine signaling which leads to direct inhibition of IL-13-activated STAT6 and finally repression of OPN expression, therefore preventing disease progression [86].…”