Synergistic Effect of Granulocyte-Macrophage Colony-Stimulating Factor and 1,25-Dihydroxyvitamin D3 on the Differentiation of the Human Monocytic Cell Line U937

Abstract

The human monoblastlike cell line U937 can be induced to differentiate by a variety of agents including gamma-interferon, phorbol esters, retinoic acid, and 1,25-dihydroxyvitamin D3 (VD3). Incubation of U937 with 1 to 1,000 units of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) did not induce macrophage differentiation. A synergistic effect on macrophage differentiation was observed, however, when U937 was cocultured with 10(-8) mol/L VD3 plus 50 U/mL GM-CSF. GM-CSF-plus VD3-treated cells demonstrated significant increases in OKM1 antigen expression, increased chemokinesis and chemotaxis, and increased Fc receptor-mediated erythrophagocytosis. Human peripheral blood monocyte cultures also demonstrated increased OKM1 antigen expression and chemotaxis when incubated with 50 to 500 U/mL of GM-CSF for 48 to 72 hours. VD3, however, was not necessary for the increases in effector function observed for GM-CSF-stimulated monocyte cultures. In distinction to the synergistic effect of GM-CSF on VD3-induced differentiation of U937, recombinant human granulocyte colony-stimulating factor (G-CSF) at comparable concentrations had no augmenting effect over that observed for VD3 alone. These results suggest that GM-CSF, in the presence of other physiological stimuli, can induce significant phenotypic changes in GM-CSF-nonresponsive cells of the monocytic lineage and can increase the effector functions of GM-CSF-responsive peripheral blood monocyte cultures.