Up-regulation of EP2 and EP3 receptors in human tolerogenic dendritic cells boosts the immunosuppressive activity of PGE2

Abstract

Dendritic cells (DCs) are APCs essential in regulating the immune response. PGE, produced during inflammation, has a pivotal role in the maturation of DCs and, therefore, is vital for the immune response. The large variety of biologic functions governed by PGE is mediated by its signaling through 4 distinct E-type prostanoid (EP) receptors. Immunogenic DCs express EP and EP, which mediate the PGE signaling. However, the expression and function of EP receptors in human tolerogenic DCs (tol-DCs), which present an inhibitory phenotype, have not yet, to our knowledge, been assessed. To clarify the role of EP receptors in tol-DCs, we examined the expression of different EP receptors and their effect using selective agonists in human cells. We find that EP and EP expression are up-regulated in in vitro-generated tol-DCs compared with mature DCs (mDCs). Activation of EP-EP has a direct effect on the surface expression of costimulatory molecules and maturation receptors, such as CD80, CD83, and CD86 or MHCII and CCR7 in tol-DCs, the latter being exclusively modulated by PGE-EP signaling. Importantly, we find that EP and EP receptors are involved in tolerance induction through IL-10 production by tol-DCs. These results are in sharp contrast with the inflammatory role of EP Moreover, we show that DCs generated in the presence of agonists for EP receptors, induce naive T cell differentiation toward polarized Th1/Th17 cells. Given the differential effects of EP receptors, our results suggest that EP receptor agonist/antagonists might become relevant novel drug templates to modulate immune response.

The Regulatory Role of the Oral Commensal Streptococcus mitis on Human Monocytes

“…IL‐23 is also an important pro‐inflammatory cytokine known for its role in the generation and maintenance of IL‐17‐producing T cells and neutrophil recruitment through the IL‐23/IL‐17 axis. In addition, EP4‐mediated IL‐23 upregulation is accompanied by downregulation of IL‐12 , and this concurs with results from our microarray set where transcription of IL12 was inhibited. In the light of this, our earlier findings of a S. mitis ‐induced memory Th17 response together with the current findings of an S. mitis ‐mediated secretion of PGE2 and transcription of PTGER4 , IL23, IL1B and IL6 indicate that S. mitis can promote Th17 responses.…”

“…PTGER4 encodes the EP4 receptor that mostly promotes anti‐inflammatory effects of PGE2 . Recently, however, EP4 was also proposed to mediate pro‐inflammatory effects as it is shown to be directly involved in inhibition of IL‐10 while triggering IL‐23 secretion in human tolerogenic dendritic cells . In contrast, we found that S. mitis triggers increased secretion of PGE2 and IL‐10 as well as increased transcription of EP4 and IL‐23.…”

“…In T cells, PGE2 both inhibits proliferation as well as promotes maturation and activation of Th17 cells through EP4‐mediated IL‐23 expression in dendritic cells and IL‐23R expression in T cells . IL‐23 transcription was found to be increased in the monocytes exposed to S. mitis, and this might be related to the increased transcription of PTGER4 as EP4 is directly linked to IL‐23 production . IL‐23 is also an important pro‐inflammatory cytokine known for its role in the generation and maintenance of IL‐17‐producing T cells and neutrophil recruitment through the IL‐23/IL‐17 axis.…”

“…Yet another role for PGE2 and EP4 is regulation of CCR7 , a chemokine receptor involved in migration to secondary lymphoid organs (SLOs). The currently observed increased expression of CCR7 and PD‐L1, and the simultaneous deactivation of PECAM1 and ITGB2 in response to S. mitis , indicates that monocytes may migrate to the SLOs and promote tolerance.…”

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

“…Prostaglandin E2 (PGE2) receptor 2 subtype (EP2) is a G protein-coupled plasma membrane receptor for PGE2, which acts through numerous signaling pathways to regulate various physiological functions, including tumor occurrence, invasion and metastasis, angiogenesis, chronic inflammation, tumor immunity and cell apoptosis (1). Recently, various studies have focused on identifying the specific EP2 receptors and signaling pathways that regulate the pleiotropic activities of the cyclooxygenase-2 (cOX-2)/PGE2/EP2 pathway (2)(3)(4)(5).…”