Cyclooxygenase-2-Issued Prostaglandin E2 Enhances the Production of Endogenous IL-10, Which Down-Regulates Dendritic Cell Functions

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Abstract
PGE2 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 PGE2 biosynthetic capacity of bone marrow-derived DC (BM-DC) and the effects of PG on the APC. We observed that BM-DC produce PGE2 and other proinflammatory mediators, such as leukotriene B4 and NO, after LPS exposure. Constitutively present in BM-DC, cyclooxygenase (COX)-1 did not contribute significantly to the total pool of PGE2 compared with the LPS-induced COX-2-produced PGE2. Treatment of BM-DC with exogenous PGE2 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 PGE2 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 B4 or NO. In view of the potential of PGE2 to stimulate IL-10, we examined the possibility that the suppressive effect of PGE2 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 PGE2 were totally reversed by anti-IL-10. We conclude that COX-2-mediated PGE2 up-regulates IL-10, which down-regulates IL-12 production and the APC function of BM-DC.