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Am J Physiol Lung Cell Mol Physiol 285: L1132-L1136, 2003. First published August 1, 2003; doi:10.1152/ajplung.00216.2003
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PU.1 regulation of human alveolar macrophage differentiation requires granulocyte-macrophage colony-stimulating factor

Tracey L. Bonfield,1 Baisakhi Raychaudhuri,1 Anagha Malur,1 Susamma Abraham,1 Bruce C. Trapnell,3 Mani S. Kavuru,1 and Mary Jane Thomassen1,2

Departments of 1Pulmonary and Critical Care Medicine and 2Cell Biology, The Cleveland Clinic Foundation, Cleveland 44195-5038; and 3Department of Pediatric Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Submitted 3 July 2003 ; accepted in final form 31 July 2003

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is critically implicated in lung homeostasis in the GM-CSF knockout mouse model. These animals develop an isolated lung lesion reminiscent of pulmonary alveolar proteinosis (PAP) seen in humans. The development of the adult form of human alveolar proteinosis is not due to the absence of a GM-CSF gene or receptor defect but to the development of an anti-GM-CSF autoimmunity. The role of GM-CSF in the development of PAP is unknown. Studies in the GM-CSF knockout mouse have shown that lack of PU.1 protein expression in alveolar macrophages is correlated with decreased maturation, differentiation, and surfactant catabolism. This study investigates PU.1 expression in vitro and in vivo in human PAP alveolar macrophages as well as the regulation of PU.1 by GM-CSF. We show for the first time that PU.1 mRNA expression in PAP bronchoalveolar lavage cells is deficient compared with healthy controls. PU.1-dependent terminal differentiation markers CD32 (FC{gamma}II), mannose receptor, and macrophage colony-stimulating factor receptor (M-CSFR) are decreased in PAP alveolar macrophages. In vitro studies demonstrate that exogenous GMCSF treatment upregulated PU.1 and M-CSFR gene expression in PAP alveolar macrophages. Finally, in vivo studies showed that PAP patients treated with GM-CSF therapy have higher levels of PU.1 and M-CSFR expression in alveolar macrophages compared with healthy control and PAP patients before GM-CSF therapy. These observations suggest that PU.1 is critical in the terminal differentiation of human alveolar macrophages.

PU-1; c-fms; alveolar proteinosis


Address for reprint requests and other correspondence: M. J. Thomassen, Dept. of Pulmonary and Critical Care Medicine, 9500 Euclid Ave., Cleveland Clinic Foundation, Desk A90, Cleveland, OH 44195-5038 (E-mail: thomasm{at}ccf.org).




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