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J. Biol. Chem., Vol. 281, Issue 8, 5058-5064, February 24, 2006

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Human Alveolar Macrophages Are Deficient in PTEN

THE ROLE OF ENDOGENOUS OXIDANTS^*

From the Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242

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_3,4,5P3), 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.

Received for publication, August 15, 2005 , and in revised form, December 15, 2005.

^* This work was supported by a Veterans Affairs Merit Review grant, National Institutes of Health Grants HL-60316, HL-077431, and HL-04428, and National Center for Research Resources, National Institutes of Health Grant RR00059 from the General Clinical Research Centers Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Pulmonary, Critical Care, and Occupational Medicine, 100 Eckstein Medical Research Bldg., Iowa City, IA 52242. Tel.: 319-384-7123; Fax: 319-335-6530; E-mail: dawn-flaherty{at}uiowa.edu.

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