Cytokine Regulation of Human Monocyte Differentiation in Vitro: The Tumor-Cytotoxic Phenotype Induced by Macrophage Colony-stimulating Factor Is Developmentally Regulated by y-Interferon

In this study we continue our examination of the unique form of antibody-dependent antitumor cytotoxicity (ADCC) which develops when human monocytes are exposed to macrophage colony-stimulating factor (MCSF) in vitro. This form of ADCC is not present in fresh monocytes and emerges only as monocytes differentiate into monocyte-derived macrophages (MDM). We now report that the presence of y-interferon (IFN-y) during this period of differentiation markedly affects the development of MCSF-induced cytotoxicity. The addition of IFN-y on day 0 resulted in a pronounced dose-dependent inhibition of ADCC measured on day 7 (mean inhibition, 76 12%; range, 66-94%). MDM exposed to MCSF plus IFN-y required 3-10-fold higher effector to target cell ratios to achieve a level of cytotoxicity comparable to that of MDM cultured with MCSF alone. This inhibitory effect was attributable to an IFN-γ-induced shift in the basic mechanism of target cell killing, away from the phagocytic form normally seen with MCSF and toward a significantly less effective extracellular form. In order to influence ADCC, IFN-y had to be present prior to the onset of differentiation; if it was added later it had progressively less effect, and if it was added after differentiation was complete it was inactive. The modulatory effects of IFN-y also extended to a number of other developmentally regulated attributes. MDM cultured with MCSF normally acquired a characteristic morphology and mmunophenotype, reentered the cell cycle, and changed functionally from accessory cells for mitogen-induced lymphocyte activation to suppressor cells. The presence of IFN-y prevented the emergence of each of these attributes. Despite these negative effects, MDM exposed to IFN-y remained viable, continued to bind and internalize MCSF, and displayed superior accessory cell function and oxidative burst activity. Taken together, our findings suggest that human monocytes are capable of following at least two distinct differentiation pathways in response to the local cytokine environment, with significant impact on the resultant macrophage phenotype in general and antitumor cytotoxicity in particular.