1,25 Dihydroxyvitamin D3-dependent inhibition of growth or killing of Mycobacterium avium complex in human macrophages is mediated by TNF and GM-CSF

Abstract

Vitamin D₃ (D₃) has been shown to activate several macrophage functions. To determine whether D₃ could activate macrophages to kill or inhibit intracellular growth of Mycobacterium avium complex (MAC), human monocyte-derived macrophages were treated with D₃ (10⁻⁷, 10⁻⁸, and 10⁻⁹M) 24 hr before or for 48 hr after MAC infection. All three concentrations were associated with inhibition of growth or killing of MAC in a dose-dependent fashion (28 ± 4% and 22 ± 3% of killing and inhibition of growth, respectively, at pharmacological concentrations) when added to the monolayer before injection or 60.4 ± 6%, 50.4 ± 3%, and 41.4 ± 6%, respectively, when added to the monolayers after infection. We found that D₃-treated macrophages produced increased concentrations of tumor necrosis factor (TNF) and granulocyte-monocyte colony stimulating factor (GM-CSF). Subsequently, macrophages were activated by D₃ in the presence of anti-TNF or anti-GM-CSF antibody: At 10⁻⁹M of D₃ there was no inhibition of D₃-dependent macrophage activation by anti-TNF antibody, whereas anti-GM-CSF antibody was associated with 100% inhibition. At 10⁻⁸M of D₃, anti-TNF antibody inhibited 35 ± 6% of killing, and anti-GM-CSF antibody was associated with 100% inhibition. At 10⁻⁷M of D₃, anti-TNF antibody inhibited 58 ± 4% and anti-GM-CSF antibody 89 ± 3% of killing. D₃ treatment is associated with anti-MAC activity in human macrophages, and this activity appears to be mediated by both TNF and GM-CSF.