title: Human alveolar macrophages are deficient in PTEN. The role of endogenous oxidants.
abstract: Human alveolar macrophages play a critical role in host defense and in the development of inflammation and fibrosis in the lung. Unlike their precursor cells, blood monocytes, alveolar macrophages are long-lived and tend to be resistant to apoptotic stimuli. In this study, we examined the role of differentiation in altering baseline phosphatidylinositol (PI) 3-kinase/Akt activity. We found that differentiation increased activity of pro-survival PI 3-kinase/Akt while decreasing amounts of the negative PI 3-kinase regulator, PTEN. PTEN is a lipid phosphatase with activity against phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3), the major bioactive product of PI 3-kinase. Examining in vivo differentiation of alveolar macrophages (by comparing blood monocytes to alveolar macrophages from single donors), we found that differentiation resulted in increased baseline reactive oxygen species (ROS) in the alveolar macrophages. This led to a deficiency in PTEN, increased activity of Akt, and prolonged survival of alveolar macrophages. These data support the hypothesis that alterations in ROS levels contribute to macrophage homeostasis by altering the balance between PI 3-kinase/Akt and the phosphatase, PTEN.
authors.affiliation: Division of Pulmonary, Critical Care and Occupational Medicine, Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA. dawn-flaherty@uiowa.edu
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Flaherty
authors.forename: Martha M
authors.initials: MM
authors.lastname: Monick
authors.forename: Sara L
authors.initials: SL
authors.lastname: Hinde
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D015153:Blotting, Western; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D015536:Down-Regulation; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005822:Genetic Vectors; D006801:Humans; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D016877:Oxidants / Q000737:chemistry* / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004791:Enzyme Inhibitors; D016877:Oxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase