Human monocytes constitutively express the platelet-activating factor receptor (hPAF-R). In this report, we have investigated the modulation of hPAF-R by IFN-gamma. Treatment of monocytes with IFN-gamma caused a time- and concentration-dependent accumulation of hPAF-R mRNA. In contrast, IFN-alpha was inactive. The effect of IFN-gamma was rapid, evident by 1 h of stimulation and reaching a maximum after 2 h. The high level of hPAF-R mRNA was maintained for at least 24 h. Flow cytometry analysis revealed that monocytes treated with IFN-gamma had a two- to sixfold increase in PAF receptor expression at the cell surface, when compared with untreated cells. The increase in hPAF-R expression was associated with an augmented response of IFN-gamma-treated cells to PAF in terms of cytosolic calcium ([Ca2+]i) variations. The IFN-gamma-dependent accumulation of hPAF-R mRNA was not due to the stabilization of hPAF-R mRNA, as shown by unchanged hPAF-R mRNA t1/2. Pretreatment of monocytes with actinomycin D, however, completely abrogated the effect of IFN-gamma, suggesting a transcriptional regulation. Moreover, the up-regulation of hPAF-R mRNA by IFN-gamma was independent of de novo protein synthesis since cycloheximide, an inhibitor of protein synthesis, did not affect this up-regulation. These studies are the first report showing that IFN-gamma regulates hPAF-R gene expression in human monocytes, by a mechanism suggesting transcriptional regulation. This may represent a prototypic example of regulation by lymphocyte-derived cytokines of lipid mediator receptors in myeloid cells, thus adding a novel element in the interrelationship between immune and inflammatory responses.