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

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

Lozano, Juan Jose¹  Borgman, Kyra J. E.¹  tez-Ribas, Daniel¹  Españ⁶  Garcia-Parajo, Maria F.⁷  Cabezó⁷  a, Carolina⁸  n, Raquel^1,11  Bení^1,11 

[1] Catalana de Recerca i Estudis Avanç..Department of Immunology, Hospital Clinic de Barcelona, Barcelona, Spain;..InsititucióCentro de InvestigacióICFO‐Institut d'investigacions BiomèInstitut de Ciencies Fotoniques, Barcelona Institute of Science and Technology, Barcelona, Spain;ats (ICREA), Barcelona, Spain;dica en Red, Enfermedades Hepádiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;n Biométicas y Digestivas (CIBERehd), Barcelona, Spain

关键词: EP receptors;    immune tolerance;    prostanoid receptors;    dendritic cells;    signalling;   

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Dendritic cells (DCs) are APCs essential in regulating the immune response. PGE₂, 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 PGE₂ is mediated by its signaling through 4 distinct E-type prostanoid (EP) receptors. Immunogenic DCs express EP₂ and EP₄, which mediate the PGE₂ 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 PGE₂–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.

【 授权许可】

CC BY