PGE 2 is a well-known immunomodulator produced in the immune response by APCs, such as dendritic cells (DCs), the most potent APC of the immune system. We investigated the PGE 2 biosynthetic capacity of bone marrow-derived DC (BM-DC) and the effects of PG on the APC. We observed that BM-DC produce PGE 2 and other proinflammatory mediators, such as leukotriene B 4 and NO, after LPS exposure. Constitutively present in BM-DC, cyclooxygenase (COX)-1 did not contribute significantly to the total pool of PGE 2 compared with the LPS-induced COX-2-produced PGE 2. Treatment of BM-DC with exogenous PGE 2 induced the production of large amounts of IL-10 and less IL-12p70. In addition, selective inhibition of COX-2, but not COX-1, was followed by significant decrements in PGE 2 and IL-10, a concomitant restoration of IL-12 production, and an enhancement of DC stimulatory potential. In contrast, we found no demonstrable role for leukotriene B 4 or NO. In view of the potential of PGE 2 to stimulate IL-10, we examined the possibility that the suppressive effect of PGE 2 is mediated via IL-10. We found that exogenous IL-10 inhibits IL-12p70 production in the presence of NS-398, a COX-2 selective inhibitor, while the inhibitory effects of PGE 2 were totally reversed by anti-IL-10. We conclude that COX-2-mediated PGE 2 up-regulates IL-10, which down-regulates IL-12 production and the APC function of BM-DC.