Peroxisome proliferator-activated receptor-γ regulates the expression of alveolar macrophage macrophage colony-stimulating factor

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-gamma (PPAR gamma), is severely deficient in both human PAP and the GM-CSF knockout mouse. To investigate the role of PPAR gamma in alveolar macrophage homeostasis, we generated myeloid-specific PPAR gamma knockout mice using the Lys-Cre method to knock out the floxed PPAR gamma gene. Similar to the GM-CSF-deficient mouse, absence of alveolar macrophage PPAR gamma 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 gamma prevented LPS-stimulated M-CSF production in RAW 264.7 cells, an effect that was abrogated by a specific PPAR gamma antagonist, GW9662. Use of proteasome inhibitor, MG-132 or a PPAR gamma agonist, pioglitazone, prevented LPS-mediated M-CSF induction. Using chromatin immunoprecipitation, we found that PPAR gamma is capable of regulating M-CSF through transrepression of NF-kappa B binding at the promoter. Gel-shift assay experiments confirmed that pioglitazone is capable of blocking NF-kappa 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-kappa B and PPAR gamma.