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RATIONALE: The host-protective role of alpha-1-antitrypsin (AAT) against mycobacteria may be partly attributed to its binding to the cytoplasmic glucocorticoid receptor (GR) that results in gene regulation in macrophages that favors killing of ingested mycobacteria. The AAT-GR complex was found to be significantly responsible for limiting Mycobacterium avium complex (MAC) burden in macrophages; this host-protective function of AAT-GR is due, in part, to induction of COLONY STIMULATING FACTOR-2 (CSF-2) gene which encodes for granulocyte-monocyte colony stimulating factor (GM-CSF). METHODS: To better understand the role of AAT-GR binding during mycobacterial infection, we performed bulk RNA sequencing (RNA-seq) on four different groups of cells: (i) control THP-1 cells (THP-1control); (ii) THP-1control cells infected with Mycobacterium intracellulare (MAC); (iii) THP-1control cells incubated with MAC + AAT; and (iv) THP-1 cells knocked down for GR (THP-1GR-KD) incubated with MAC + AAT. RESULTS: Our analyses revealed that MAC infection significantly upregulated 1,977 genes and significantly downregulated 2,303 genes in THP-1control cells. Additionally, AAT significantly upregulated 1,200 genes and downregulated 890 genes in MAC-infected THP-1control cells. Furthermore, the regulation of 1,624 genes that are regulated by AAT+GR in THP-1control cells was augmented in THP-1GR-KD cells, indicating that the regulation of these genes by AAT+MAC is inhibited by GR. Conversely, the regulation of 1,683 genes by AAT+MAC in THP-1control cells was attenuated in THP-1GR-KD cells, indicating that the regulation of these genes by AAT+MAC is enhanced by GR. MAC also induced both CSF2 (GM-CSF) and CSF1 (encodes for monocyte colony stimulating factor, M-CSF) expression. Whereas AAT inhibited MAC-induced M-CSF mRNA was dependent on GR, this inhibition of M-CSF protein was not dependent on GR. In contrast, AAT did not inhibit MAC-induced CSF2 (GM-CSF) expression. Since either MAC or AAT induced GM-CSF expression in macrophages, further investigation revealed that AAT-inhibition of cell-associated MAC burden was abrogated upon neutralization of endogenous GM-CSF. CONCLUSIONS: The ability of AAT to induce GM-CSF and to inhibit MAC-induced M-CSF may skew macrophages to a phenotype that is better endowed to control mycobacterial infection.