Fc-gamma receptor III (Fc gamma RIII, CD16) type A is expressed on natural killer cells, on a small subset of peripheral blood monocytes and on mature macrophages. Along with differentiation into macrophages, monocytes will express Fc gamma RIII when cultured with transforming growth factor-beta (TGF-beta). In view of the involvement of granulocyte-macrophage colony-stimulating factor (GM-CSF) in myeloid cell differentiation, we investigated the effect of this cytokine on Fc gamma RIII expression in cultures of peripheral blood monocytes. GM-CSF antagonized TGF-beta-induced expression of Fc gamma RIII on monocytes in vitro in a dose-dependent way. The effect of GM-CSF persisted in cultures until at least day 7. The suppression was at the mRNA level, as shown by Northern analyses with a CD16 specific probe, and the signalling pathway involved tyrosine kinase activity. Interferon-gamma and interleukin-2 had no effect on the induced expression of Fc gamma RIII by TGF-beta, while interleukin-4, similar to GM-CSF, antagonized this induction. Our findings suggest that regulatory cytokine networks can drive monocytes into different effector functions and differentiation pathways.