Human alveolar macrophages are deficient in PTEN: The role of endogenous oxidants

doi:10.1074/jbc.M508997200

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Papers In Press, published online ahead of print December 21, 2005
J. Biol. Chem, 10.1074/jbc.M508997200
Submitted on August 15, 2005
Revised on December 15, 2005
Accepted on December 21, 2005

Human alveolar macrophages are deficient in PTEN: The role of endogenous oxidants

Dawn M. Flaherty, Martha M. Monick, and Sara L. Hinde

Internal Medicine, Division of Pulmonary, Critical Care, and, University of Iowa, Iowa City, IA 52242

Corresponding Author: dawn-flaherty{at}uiowa.edu

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 3-kinase (PI3-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 (PI3,4,5P3), the major bioactive product of PI3-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. This data supports the hypothesis that alterations in ROS levels contribute to macrophage homeostasis by altering the balance between PI 3-kinase/Akt and the phosphatase, PTEN.

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