Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
ICFO-Institut de Ciencies Fotoniques, Barcelona Institute of Science and Technology, Barcelona, Spain.
J Leukoc Biol. 2017 Sep;102(3):881-895. doi: 10.1189/jlb.2A1216-526R. Epub 2017 Jun 19.
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.
树突状细胞（DCs）是调节免疫反应的必需 APC。前列腺素 E（PGE）在炎症期间产生，在 DC 的成熟中起着关键作用，因此对免疫反应至关重要。PGE 通过其与 4 种不同的 E 型前列腺素（EP）受体的信号传导来介导其广泛的生物学功能。免疫原性 DC 表达 EP 和 EP，它们介导 PGE 信号传导。然而，我们尚未评估在具有抑制表型的人类耐受性 DC（tol-DC）中 EP 受体的表达和功能，就我们所知。为了阐明 EP 受体在 tol-DC 中的作用，我们使用选择性激动剂检查了不同 EP 受体的表达及其在人类细胞中的作用。我们发现，与成熟 DC（mDC）相比，体外生成的 tol-DC 中 EP 和 EP 的表达上调。EP-EP 的激活对共刺激分子和成熟受体（如 CD80、CD83 和 CD86 或 MHCII 和 CCR7）的表面表达具有直接影响，后者仅由 PGE-EP 信号传导调节。重要的是，我们发现 EP 和 EP 受体通过 tol-DC 产生的 IL-10 参与诱导耐受。这些结果与 EP 的炎症作用形成鲜明对比。此外，我们表明，在 EP 受体激动剂存在下生成的 DC 诱导幼稚 T 细胞向极化 Th1/Th17 细胞分化。鉴于 EP 受体的差异作用，我们的结果表明 EP 受体激动剂/拮抗剂可能成为调节免疫反应的新型药物模板。
