CONICET | Buscador de Institutos y Recursos Humanos

Monocytes infiltrate infection sites and tumors, where they sense microenvironmental cues and become dendritic cells (DCs) or macrophages that will be key players of the ensuing immune response. TGF-β and prostaglandin E2 (PGE2) are two ubiquitous immunomodulators, known to influence differentiation of DCs. Presence of TGF-β during differentiation of DCs with IL-4 and GM-CSF leads to DCs with enhanced inflammatory properties. Conversely, PGE2 drives differentiation towards generation of myeloid-derived suppressor cells.In this study we aim to investigate the impact of PGE2 on the profile induced by TGF-β during differentiation of DCs. To this end, we incubated human monocytes for 5 days with IL-4 and GM-CSF alone (control DC) or with TGF-beta (T-DCs), with or without the addition of PGE2 (10-7M) at the beginning of the culture. Compared to control DCs, T-DCs showed higher CD1a and decreased CD14 expression, as well as enhanced LPS-induced IL-12 production. Notably, LPS-induced expression of IL-10 was completely abolished. However, simultaneous addition of PGE2 led to DCs showing a CD1a-CD14+ phenotype and unable to fully mature or produce IL-12 after LPS stimulation (12 vs 1347 pg/ml in T-DCs). These DCs, which produced higher levels of IL-10 (1410 vs 35 pg/ml in T-DCs) and IDO (22 times more than T-DCs, by qPCR), elicited the expansion of CD25+FoxP3+ T cells when cultured with allogeneic CD4+ lymphocytes (17.9% vs 8.0% in T-DCs). These results indicate that the presence of PGE2 can override TGF-β signaling and drive DCs towards a tolerogenic phenotype. Furthermore, we demonstrated that inhibition of TGF-beta by PGE2 requires prostanoid receptors EP2 and EP4, elevation of cyclinc AMP and PKA activity.Taken together, these results suggest that potential TGF-β pro-inflammatory actions on myeloid differentiation in the context of tumor or inflammatory microenvironment could be masked by the simultaneous presence of PGE2.