Abstract
Inflammatory dendritic cells (DCs) are a distinct subset of DCs that derive from circulating monocytes infiltrating injured tissues. Monocytes can differentiate into DCs with different functional signatures, depending on the presence of environment stimuli. Among these stimuli, transforming growth factor-beta (TGF-β) and prostaglandin E2 (PGE2) have been shown to modulate the differentiation of monocytes into DCs with different phenotypes and functional profiles. In fact, both mediators lead to contrasting outcomes regarding the production of inflammatory and anti-inflammatory cytokines. Previously, we have shown that human semen, which contains high concentrations of PGE2, promoted the differentiation of DCs into a tolerogenic profile through a mechanism dependent on signaling by E-prostanoid receptors 2 and 4. Notably, this effect was induced despite the huge concentration of TGF-β present in semen, suggesting that PGE2 overrides the influence exerted by TGF-β. No previous studies have analyzed the joint actions induced by PGE2 and TGF-β on the function of monocytes or DCs. Here, we analyzed the phenotype and functional profile of monocyte-derived DCs differentiated in the presence of TGF-β and PGE2. DC differentiation guided by TGF-β alone enhanced the expression of CD1a and abrogated LPS-induced expression of IL-10, while differentiation in the presence of PGE2 impaired CD1a expression, preserved CD14 expression, abrogated IL-12 and IL-23 production, stimulated IL-10 production, and promoted the expansion of FoxP3+ regulatory T cells in a mixed lymphocyte reaction. Interestingly, DCs differentiated in the presence of TGF-β and PGE2 showed a phenotype and functional profile closely resembling those induced by PGE2 alone. Finally, we found that PGE2 inhibited TGF-β signaling through an action exerted by EP2 and EP4 receptors coupled to cyclic AMP increase and protein kinase A activity. These results indicate that PGE2 suppresses the influence exerted by TGF-β during DC differentiation, imprinting a tolerogenic signature. High concentrations of TGF-β and PGE2 are usually found in infectious, autoimmune, and neoplastic diseases. Our observations suggest that in these scenarios PGE2 might play a mandatory role in the acquisition of a regulatory profile by DCs.
Highlights
Dendritic cells (DCs) comprise a heterogeneous group of cells characterized by their ability to induce T cell activation and to silence T cell immune responses
We found that the presence of Prostaglandin E2 (PGE2) at the onset of the differentiation of monocytes into DCs antagonizes phenotypic and functional signatures induced by Transforming growth factor-β (TGF-β)
Analysis of DCs differentiated in the presence of both TGF-β and PGE2 revealed that PGE2 strongly antagonized the effects mediated by TGF-β in a concentration-dependent mode (Figures 1A–C)
Summary
Dendritic cells (DCs) comprise a heterogeneous group of cells characterized by their ability to induce T cell activation and to silence T cell immune responses. Inflammatory DCs show high plasticity, which enables them to induce the differentiation of CD4+ T cells into different effector profiles [2,3,4,5]. They can differentiate into tolerogenic DCs to keep the immune response under control [6]. TGF-β is known to suppress the function of effector CD4+ and CD8+ T cells, to promote the activation of naïve CD4+ T cells into a regulatory profile and to suppress the activation of natural killer cells [9,10,11]. Monocytes cultured with TGF-β (together with GM-CSF and IL-4), differentiate toward Langerhans cell (LC)-like DCs that are unable to produce IL-10 but have a great capacity to secrete IL-12 upon stimulation [17, 18]
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