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

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Susamma Abraham (Creator)

Tracey L. Bonfield (Creator)

Daniel A. Culver (Creator)

Carol F. Farver (Creator)

Mary T. Koloze (Creator)

David M. Mosser (Creator)

Mary Jane Thomassen (Creator)

Xia Zhang (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

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 GMCSF 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.

Additional Information

Publication

Other

Journal of Immunology. 181:1(July 2008) p. 235-242.

Language: English

Date: 2011

Keywords

macrophage CSF, peroxisome, pulmonary alveolar proteinosis

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