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

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.

Prostaglandin I2 Analogs Inhibit Proinflammatory Cytokine Production and T Cell Stimulatory Function of Dendritic Cells

“…It has been shown that induction of cAMP has been associated with the modulatory effects of cAMPelevating agents including db-cAMP, forskolin, and the phosphodiesterase inhibitor IBMX. These reagents inhibited IL-12, TNF-␣, and MIP-1␣, while increasing IL-10 production by BMDCs (22,38,39). A similar effect of cAMP-elevating agents has been reported on BM-derived macrophages (40).…”

“…The action of PGI 2 analogs makes them effective inhibitors of proinflammatory cytokines and chemokines and our data indicate that this inhibitory effect of PGI 2 analogs is associated with the decrease of NF-B activity. PGE 2 is another PG that has anti-inflammatory properties (22,38,49). Similar to the effect of PGI 2 analogs, PGE 2 has been shown to inhibit IL-12, TNF-␣, and IL-6 production by BMDCs, suppress MHC class II expression, and enhance IL-10 production (22,29,38,39).…”

“…PGE 2 is another PG that has anti-inflammatory properties (22,38,49). Similar to the effect of PGI 2 analogs, PGE 2 has been shown to inhibit IL-12, TNF-␣, and IL-6 production by BMDCs, suppress MHC class II expression, and enhance IL-10 production (22,29,38,39). Studies showed that DCs may be activated to produce high levels of proinflammatory cytokines and remain at sites of inflammation or develop into CCR7-expressing cells that allow them to migrate to the draining lymph nodes and induce Ag-specific immune responses (50,51).…”

Altered maturation of peripheral blood dendritic cells in patients with breast cancer

“…Moreover, in vitro tumour supernatants are able to promote rapid maturation of DCs with upregulation of CD83 molecule expression (Kiertscher et al, 2000). Finally, factors present in the tumour environment in vivo, such as polyamines or prostaglandins, might also interfere with the maturation and/or function of DCs (Haskò et al, 2000;Harizi et al, 2002). In fact, we found that exposure of in vitro maturing DCs to spermine enhanced the expression of CD83, suggesting that this tumour-derived polyamine could be involved in the phenotypic maturation of PB DCs observed in vivo.…”

Prostaglandins Inhibit 5-Lipoxygenase-Activating Protein Expression and Leukotriene B4 Production from Dendritic Cells Via an IL-10-Dependent Mechanism

“…For many years, macrophages have been considered as a major source of eicosanoids. More recently, we have reported that the in vitro generated dendritic cells (DC) produce a full range of eicosanoids, in particular PGE 2 and LTB 4 (4).…”