Interferon-gamma (IFN-gamma) stimulates the development of monocytic features in human myeloid precursors. Because transcriptional regulation of IFN-gamma and the pituitary hormone prolactin (PRL) has been described to involve common Jak-STAT pathways, we addressed here the question of whether PRL plays a role in monoblastic (U937) cell growth and macrophage maturation. In contrast to IFN-gamma, PRL did not affect U937 cell growth nor induction of differentiation as assessed by the unchanged cell surface expression of maturation markers CD11b and HLA-DR class II. However, PRL in synergy with IFN-gamma inhibited, in a time- and dose-dependence, proliferation of U937 cells without influencing their maturation induced by IFN-gamma. IFN-gamma and PRL both affected the expression of the IFN-gamma receptor (IFN-gamma R) gene by increasing IFN-gamma R mRNA levels. The rise in IFN-gamma R transcripts was accompanied by a low but significant release of IL-6 which has previously been shown to stabilize IFN-gamma R mRNA. Moreover, a transient increase in surface expression of IFN-gamma R was observed in U937 cells treated by IFN-gamma alone or in combination with PRL, whereas no apparent modulation of cell surface IFN-gamma R was observed in cells treated with PRL. Lastly, PRL did not induce transcriptional activation in IFN-gamma inducible IRF-1 and Fc gamma RI genes in U937 cells. Together, our data indicate that IL-6 secretion and increased expression of the IFN-gamma R gene correlate with U937 cell growth arrest induced by IFN-gamma and PRL, probably through a signaling mechanism which does not involve the Stat 1/IRF-1 pathway.