Peroxisome Proliferator-Activated Receptor-γ Regulates the Expression of Alveolar Macrophage Macrophage Colony-Stimulating Factor

Abstract

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

Peroxisome proliferator-activated receptor-γ interrupts angiogenic signal transduction via transrepression of platelet-derived growth factor-β receptor in hepatic stellate cells

“…Furthermore, our data clearly indicated a mechanism of PPARc transrepression of PDGF-bR. There are reports that activated PPARc could interfere with the activity and function of other transcription factors such as NF-kB and AP-1, leading to disruption of their binding to target gene promoters and thereby to transcription repression (Bonfield et al, 2008;BassaganyaRiera et al, 2010). This transcriptional model may underlie the ability of PPARc to attenuate HSC angiogenic properties observed in the present study.…”

Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung

“…Importantly, transduction of GM-CSF KO alveolar macrophages with PU.1 in vitro reverses their functional impairment (20). PPARγ is also highly expressed in alveolar macrophages and, similarly to GM-CSF KO mice, PPARγ KO mice develop PAP (21). Immunohistological staining of lung sections revealed the presence of numerous hCD68 + cells with a typical intra-alveolar location, consistent with human alveolar macrophages, in engrafted h/h mice (Fig.…”

Peroxisome Proliferator-activated Receptor γ Negatively Regulates IFN-β Production in Toll-like Receptor (TLR) 3- and TLR4-stimulated Macrophages by Preventing Interferon Regulatory Factor 3 Binding to the IFN-β Promoter

“…In macrophages, PPAR-␥-mediated repression of LPS-induced iNOS gene expression has been demonstrated. PPAR-␥ has been reported to regulate the expression of macrophage colonystimulating factor in alveolar macrophages (18). PPAR-␥ agonist has been shown to down-regulate IL-17 expression in a murine model of allergic airway inflammation (19).…”