title: Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Respiratory Diseases and Tuberculosis, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkok, 10700, Thailand. kittipong.man@mahidol.ac.th.
authors.forename: Kittipong
authors.initials: K
authors.lastname: Maneechotesuwan
authors.affiliation: Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Kanda
authors.initials: K
authors.lastname: Kasetsinsombat
authors.affiliation: Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Adisak
authors.initials: A
authors.lastname: Wongkajornsilp
authors.affiliation: Airway Section, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism; D000243:Adenosine Deaminase / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D000073865:Cigarette Smoking / Q000009:adverse effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015536:Down-Regulation; D005260:Female; D005541:Forced Expiratory Volume; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008297:Male; D008875:Middle Aged; D053495:Osteopontin / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000627:therapeutic use*; D012906:Smoke / Q000009:adverse effects*; D013183:Sputum / Q000201:enzymology / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D058851:GPI-Linked Proteins; C578095:IL13 protein, human; D018793:Interleukin-13; C506895:SPP1 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D012906:Smoke; D053495:Osteopontin; D019821:Simvastatin; D015720:5'-Nucleotidase; C548241:NT5E protein, human; C548482:ADA protein, human; D000243:Adenosine Deaminase
keywords: Adenosine deaminase; COPD; IL-13; Osteopontin; Simvastatin