Up-regulation of EP 2 and EP 3 receptors in human tolerogenic dendritic cells boosts the immunosuppressive activity of PGE 2 .

Dendritic cells (DCs) are APCs essential in regulating the immune response. PGE ₂ , 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 ₂ is mediated by its signaling through 4 distinct E-type prostanoid (EP) receptors. Immunogenic DCs express EP ₂ and EP ₄ , which mediate the PGE ₂ 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 ₂ and EP ₃ expression are up-regulated in in vitro-generated tol-DCs compared with mature DCs (mDCs). Activation of EP ₂ -EP ₄ 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 ₂ -EP ₄ signaling. Importantly, we find that EP ₂ and EP ₃ 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 ₄ 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.
(© Society for Leukocyte Biology.)