PGE2 transiently enhances DC expression of CCR7 but inhibits the ability of DCs to produce CCL19 and attract naive T cells

Abstract

Prostaglandin E 2 (PGE 2 ) is an inflammatory mediator often used to increase CCR7 expression in the dendritic cells (DCs) used as cancer vaccines and to enhance their responsiveness to lymph nodeassociated chemokines. Here, we show that high surface expression of CCR7 on PGE 2 -matured DCs is associated with their suppressed production of the endogenous CCR7 ligand, CCL19, and is reversible by exogenous CCL19. In contrast to the PGE 2 -matured DCs, DCs matured in the presence of toll-like receptor (TLR) ligands and interferons produce high levels of both CCL19 and CCR7 mRNA/ protein, but show selectively reduced expression of surface CCR7, which is compensated after DC removal from the CCL19-rich maturation environment. In accordance with these findings, PGE 2 -matured DCs show significantly higher in vitro migratory responsiveness to lymph node-associated chemokines directly after DC generation, but not after additional short-term culture in vitro, nor in vivo in patients injected with 111 indium-labeled DCs. The differences in CCL19-producing ability imprinted during DC maturation result in their different abilities to attract CCR7 ؉ naive T cells. Our data help to explain the impact of PGE 2 on CCR7 expression in maturing DCs and demonstrate a novel mechanism of regulatory activity of PGE 2 , mediated by the inhibition of DCs ability to attract naive T cells. (Blood. 2010;116(9):1454-1459) IntroductionProstaglandin E 2 (PGE 2 ) is an inflammatory mediator with suppressive activity at several levels of the immune response. 1-3 PGE 2 selectively impairs the production of interleukin-2 (IL-2) and interferon-␥ (IFN␥) in T cells, 4,5 inhibits the responsiveness to T cell-activating and Th1-driving cytokines such as IL-2 and IL-12p70, 6,7 blocks the production of dendritic cell (DC)-produced proinflammatory cytokines, including IL-12p70, [8][9][10] and induces the production of IL-12R antagonist IL-12p40 homodimer. 11,12 Recently, PGE 2 has been also shown to promote the ability of DCs to preferentially attract the inhibitory regulatory T cell (Treg) subset of CD4 ϩ T cells 13 and to directly promote the development of Tregs. 14,15 In apparent contrast to these suppressive functions, PGE 2 also has been reported to synergize with tumor necrosis factor-␣ (TNF␣) in the induction of DC maturation 10,16 and in promoting CCR7 expression and the chemotactic responsiveness of DCs to CCL19 and CCL21, 17-19 the 2 CCR7 ligands known to promote DC entry into lymph nodes. [20][21][22] These observations opened the possibility that PGE 2 may also support the induction of antigen-specific immune responses by promoting the migration of Ag-carrying DCs to the draining lymph nodes and their interaction with lymph node-based naive and central memory T cells. Based on these observations, PGE 2 is frequently included in the cytokine cocktails 16 used to induce mature DCs for clinical use as vaccines against cancer. 23 Taking into account these apparently paradoxical effects of PGE 2 on DC functions and guided by the observations from...

An Inflammatory Mediator, Prostaglandin E2, in Colorectal Cancer

“…Similarly, PGE 2 inhibits secretion of IFNα by Toll-like receptor (TLR)-activated PDCs via EP2/4, which results in reduction of Th1 cytokine secretion and induction of Th2 cytokine secretion by T cells (Fabricius et al, 2010). PGE 2 also inhibits the ability of DCs to produce CCL19 that attracts CCR7-expressing naïve CD4 + T cells (Muthuswamy et al, 2010). More interestingly, PGE 2 has been recently showed to redirect the differentiation of human DCs into monocytic MDSCs (Obermajer et al, 2011a).…”

The role of prostaglandin E2 receptor signaling of dendritic cells in rheumatoid arthritis

“…PGE2-treated DCs migrate more deeply into the center of the lymph nodes to the sites of T-cell priming in the mice [56]. However, clinical studies comparing the in vivo migratory capacity of differentially matured human DCs did not reveal any migratory advantage of DCs conferred by exogenous PGE2 [54,57]. A recent study in PGES-1-deficient murine model exhibited an abrogation of PGE2 synthesis by DCs and their altered cytokine profile, but it did not reveal any impact on their maturation status or migratory function [58], which indicated that DC maturation and effective lymph node migration could occur in the absence of PGE2.…”

“…And the signaling mechanisms involved in PGE2-induced MMP-9 expression in DCs are mediated through the EP2/EP4-cAMP-PKA/PI3K-ERK signaling pathway [53]. However, recent data demonstrated that PGE2 transiently enhances DC expression of CCR7 but inhibits the ability of DCs to produce CCL19 and attracts naïve T cells and are rapidly compensated after DC removal from the CCL19 rich maturation environment [54]. Furthermore, the balance between MMP and tissue inhibitors of metalloproteinases (TIMP) has been shown to modulate DC migration.…”

CK12a, a CCL19-like Chemokine That Orchestrates both Nasal and Systemic Antiviral Immune Responses in Rainbow Trout

“…We have previously shown that HK and gut CD8α + cells express CCR7 (29) indicating that the source of cells used in our studies should not be reason why chemotaxis results were negative. Some reports have shown the importance of PGE2 on the migratory ability of CCL19 in mammalian monocytes (83–86). Thus, we also pre-activated HKLs with PGE2 but still failed to observe any chemotactic effects in vitro .…”