title: Chronic ethanol ingestion in rats decreases granulocyte-macrophage colony-stimulating factor receptor expression and downstream signaling in the alveolar macrophage.
abstract: Although it is well recognized that alcohol abuse impairs alveolar macrophage immune function and renders patients susceptible to pneumonia, the mechanisms are incompletely understood. Alveolar macrophage maturation and function requires priming by GM-CSF, which is produced and secreted into the alveolar space by the alveolar epithelium. In this study, we determined that although chronic ethanol ingestion (6 wk) in rats had no effect on GM-CSF expression within the alveolar space, it significantly decreased membrane expression of the GM-CSF receptor in alveolar macrophages. In parallel, ethanol ingestion decreased cellular expression and nuclear binding of PU.1, the master transcription factor that activates GM-CSF-dependent macrophage functions. Furthermore, treatment of ethanol-fed rats in vivo with rGM-CSF via the upper airway restored GM-CSF receptor membrane expression as well as PU.1 protein expression and nuclear binding in alveolar macrophages. Importantly, GM-CSF treatment also restored alveolar macrophage function in ethanol-fed rats, as reflected by endotoxin-stimulated release of TNF-alpha and bacterial phagocytosis. We conclude that ethanol ingestion dampens alveolar macrophage immune function by decreasing GM-CSF receptor expression and downstream PU.1 nuclear binding and that these chronic defects can be reversed relatively quickly with rGM-CSF treatment in vivo.
authors.affiliation: Atlanta Veterans Affairs Medical Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Pratibha C
authors.initials: PC
authors.lastname: Joshi
authors.forename: Lisa
authors.initials: L
authors.lastname: Applewhite
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Ritzenthaler
authors.forename: Jesse
authors.initials: J
authors.lastname: Roman
authors.forename: Alberto L
authors.initials: AL
authors.lastname: Fernandez
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Eaton
authors.forename: Lou Ann S
authors.initials: LA
authors.lastname: Brown
authors.forename: David M
authors.initials: DM
authors.lastname: Guidot
mesh_terms: D000437:Alcoholism / Q000150:complications / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D010587:Phagocytosis / Q000187:drug effects; D018410:Pneumonia, Bacterial / Q000209:etiology / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D004247:DNA; D000431:Ethanol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011518:Proto-Oncogene Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1