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Regulates the Expression of Alveolar Macrophage Macrophage Colony-Stimulating Factor
* Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44109;
Departments of Pulmonary Allergy and Critical Care, Pathobiology and Anatomic Pathology Cleveland Clinic, Cleveland, OH 44195;
Program in Lung Cell Biology and Translational Research, Division of Pulmonary and Critical Care Medicine, East Carolina University, Greenville, NC 27858; and
Department of Cellular and Molecular Biology, University of Maryland, College Park, MD 20742
Macrophage CSF (M-CSF) regulates monocyte differentiation, activation, and foam cell formation. We have observed that it is elevated in human pulmonary alveolar proteinosis (PAP) and in the GM-CSF knockout mouse, a murine model for PAP. A potential regulator of M-CSF, peroxisome proliferator-activated receptor-
(PPAR), is severely deficient in both human PAP and the GM-CSF knockout mouse. To investigate the role of PPAR in alveolar macrophage homeostasis, we generated myeloid-specific PPAR knockout mice using the Lys-Cre method to knock out the floxed PPAR gene. Similar to the GM-CSF-deficient mouse, absence of alveolar macrophage PPAR resulted in development of lung pathology resembling PAP in 16-wk-old mice, along with excess M-CSF gene expression and secretion. In ex vivo wild-type alveolar macrophages, we observed that M-CSF itself is capable of inducing foam cell formation similar to that seen in PAP. Overexpression of PPAR prevented LPS-stimulated M-CSF production in RAW 264.7 cells, an effect that was abrogated by a specific PPAR antagonist, GW9662. Use of proteasome inhibitor, MG-132 or a PPAR agonist, pioglitazone, prevented LPS-mediated M-CSF induction. Using chromatin immunoprecipitation, we found that PPAR is capable of regulating M-CSF through transrepression of NF-
B binding at the promoter. Gel-shift assay experiments confirmed that pioglitazone is capable of blocking NF-B binding. Taken together, these data suggest that M-CSF is an important mediator of alveolar macrophage homeostasis, and that transcriptional control of M-CSF production is regulated by NF-B and PPAR.
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 Address correspondence and reprint requests to Dr. Tracey L. Bonfield, Department of Pediatrics, Case Western Reserve University, 10900 Euclid Avenue, BRB-822, Cleveland, OH 44109. E-mail address: tracey.bonfield{at}case.edu
2 Abbreviations used in this paper: PPAR, peroxisome proliferator-activated receptor-; BAL, bronchoalveolar lavage; ChIP, chromatin immunoprecipitation; KO, knockout; M-CSF, macrophage CSF; PAS, periodic acid-Schiff; PAP, pulmonary alveolar proteinosis; PPRE, peroxisome proliferator response element.
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  H. Nakaya, B. D. Summers, A. C. Nicholson, A. M. Gotto Jr., D. P. Hajjar, and J. Han Atherosclerosis in LDLR-Knockout Mice Is Inhibited, but Not Reversed, by the PPAR{gamma} Ligand Pioglitazone Am. J. Pathol., June 1, 2009; 174(6): 2007 - 2014. [Abstract] [Full Text] [PDF]
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