chief function of GM-CSF in facilitating the terminal differentiation of circulating monocytes into mature alveolar macrophages was discovered after development of the GM-CSF knockout mouse, which had normal bone marrow maturation, but abnormal alveolar macrophage maturation and a phenotype that resembles pulmonary alveolar proteinosis (PAP) (Huffman et al., 1996). Consistent with the GM-CSF knockout mouse, later studies from PAP patients showed a significant decrease in PU.1 expression in their alveolar macrophages, which can be restored with exogenous GM-CSF administration (Bonfield et al., 2003). Our experiments demonstrated decreased nuclear binding of PU.1 in macrophages from alcohol-fed animals. This finding follows prior work demonstrating a down-regulation of GM-CSF receptor expression with chronic alcohol ingestion (Joshi et al., 2006;Joshi et al., 2005). Our findings in this current study complement previous studies and show that zinc supplementation, both in vitro and in vivo, restored nuclear binding of PU.1 in alveolar macrophages (Joshi et al., 2008). Therefore, a plausible conclusion is that increased PU.1 nuclear binding reflects reactivation of GM-CSF signaling and ultimately, restoration of phagocytic function.
