1,25 Dihydroxyvitamin D 3-dependent inhibition of growth or killing of Mycobacterium avium complex in human macrophages is mediated by TNF and GM-CSF

Abstract

Vitamin D 3 (D 3) has been shown to activate several macrophage functions. To determine whether D 3 could activate macrophages to kill or inhibit intracellular growth of Mycobacterium avium complex (MAC), human monocyte-derived macrophages were treated with D 3 (10 −7, 10 −8, and 10 −9 M) 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 D 3-treated macrophages produced increased concentrations of tumor necrosis factor (TNF) and granulocyte-monocyte colony stimulating factor (GM-CSF). Subsequently, macrophages were activated by D 3 in the presence of anti-TNF or anti-GM-CSF antibody: At 10 −9 M of D 3 there was no inhibition of D 3-dependent macrophage activation by anti-TNF antibody, whereas anti-GM-CSF antibody was associated with 100% inhibition. At 10 −8 M of D 3, anti-TNF antibody inhibited 35 ± 6% of killing, and anti-GM-CSF antibody was associated with 100% inhibition. At 10 −7 M of D 3, anti-TNF antibody inhibited 58 ± 4% and anti-GM-CSF antibody 89 ± 3% of killing. D 3 treatment is associated with anti-MAC activity in human macrophages, and this activity appears to be mediated by both TNF and GM-CSF.