期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 102, 期 3, 页码 881-895出版社
WILEY
DOI: 10.1189/jlb.2A1216-526R
关键词
EP receptors; immune tolerance; prostanoid receptors; dendritic cells; signalling
资金
- Instituto Carlos III [FIS PI13/01585]
- Ministerio de Economia y Competitividad
- European Regional Development Fund [IPT-090000-2010-0001]
- Consejo Interinstitucional de Ciencia y Tecnologia [CTQ2012-30930]
- Generalitat de Catalunya [2014 SGR 137]
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 EP2 and EP4, 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 EP2 and EP3 expression are up-regulated in in vitro-generated tol-DCs compared with mature DCs (mDCs). Activation of EP2-EP4 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)-EP4 signaling. Importantly, we find that EP2 and EP3 receptors are involved in tolerance induction through IL-10 production by tol-DCs. These results are in sharp contrast with the inflammatory role of EP4. 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.
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