Impairment of Growth of Listeria monocytogenes in THP-1 Macrophages by Granulocyte Macrophage Colony-Stimulating Factor: Release of Tumor Necrosis Factor–a and Nitric Oxide

Background. Listeria monocytogenes tends to survive in phagocytes. Granulocyte macrophage colony-stimulating factor (GM-CSF) protects mice against L. monocytogenes infection, and mice knocked out for the GM-CSF gene are more susceptible to these infections. Methods. THP-1 cells were used to characterize the GM-CSF receptor (binding isotherms; STAT5 phosphorylation), measure the intracellular growth of L. monocytogenes (5 h after phagocytosis), examine the influence of a 24-h incubation with GM-CSF before infection, measure the production of tumor necrosis factor (TNF)–a and the expression of nitric oxide synthase (iNOS), and evaluate the influence of anti–GM-CSF receptor (GMCSFRa) and anti—TNF-a antibodies and the addition of Nq-nitro-L-arginine methyl ester (L-NAME) and catalase. Results. THP-1 cells display functional GM-CSFRa. GM-CSF impairs the intracellular growth of L. monocytogenes to ∼65% of its value in unstimulated cells. This effect is abolished by anti–GM-CSFRa, anti–TNF-a antibodies, and catalase (and, to a lesser extent, by L-NAME). GM-CSF stimulates the release of TNF-a and the expression of iNOS. TNF-a added to unstimulated cells (even in large amounts) does not fully reproduce the impairment in the growth of L. monocytogenes caused by GM-CSF. Conclusions. GM-CSF impairs the intracellular growth of L. monocytogenes by a synergistic action of the GMCSF–triggered release of autocrine TNF-a and hydrogen peroxide and the production of NO (associated with the stimulation of the expression of iNOS).