Peroxisome proliferator-activated receptor-gamma 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 (PPARgamma), is severely deficient in both human PAP and the GM-CSF knockout mouse. To investigate the role of PPARgamma in alveolar macrophage homeostasis, we generated myeloid-specific PPARgamma knockout mice using the Lys-Cre method to knock out the floxed PPARgamma gene. Similar to the GM-CSF-deficient mouse, absence of alveolar macrophage PPARgamma 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 PPARgamma prevented LPS-stimulated M-CSF production in RAW 264.7 cells, an effect that was abrogated by a specific PPARgamma antagonist, GW9662. Use of proteasome inhibitor, MG-132 or a PPARgamma agonist, pioglitazone, prevented LPS-mediated M-CSF induction. Using chromatin immunoprecipitation, we found that PPARgamma is capable of regulating M-CSF through transrepression of NF-kappaB binding at the promoter. Gel-shift assay experiments confirmed that pioglitazone is capable of blocking NF-kappaB 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-kappaB and PPARgamma.
Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44109, USA. tracey.bonfield@case.edu
Tracey L
TL
Bonfield
Mary Jane
MJ
Thomassen
Carol F
CF
Farver
Susamma
S
Abraham
Mary T
MT
Koloze
Xia
X
Zhang
David M
DM
Mosser
Daniel A
DA
Culver
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D000077205:Pioglitazone; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020218:Response Elements; D045162:Thiazolidinediones / Q000494:pharmacology
D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D016173:Macrophage Colony-Stimulating Factor; D000077205:Pioglitazone