Macrophage activation is accompanied by reductions in prostacyclin generation and platelet-activating factor (PAF) levels, but the mechanism has not been identified. We have investigated the involvement of glucocorticoid-sensitive mechanisms and endogenous PAF in this phenomenon. The synthetic glucocorticoid, dexamethasone (1 microM) reduced basal prostacyclin and PAF generation in resident, but not in activated macrophages. PAF receptor antagonists or dexamethasone reduced the basal, but not stimulation-induced prostacyclin generation in resident macrophages. Dexamethasone and PAF antagonists did not have synergistic inhibitory effects on prostacyclin generation by resident macrophages, and the reduction was less than that which accompanies macrophage activation. Thus, differences in the effects of PAF receptor antagonists and dexamethasone compared with macrophage activation on zymosan-induced prostacyclin synthesis indicate that factors other than PAF or glucocorticoid-sensitive mechanisms contribute to this phenomenon. Subsequent experiments with culture media conditioned by resident macrophages indicated the presence of a soluble factor which increases prostacyclin generation and appears to be absent in media conditioned by activated macrophages.