CONICET | Buscador de Institutos y Recursos Humanos

Monocytes infiltrate infection sites and tumors, wherethey sense microenvironmental cues and become dendritic cells(DCs) or macrophages that will be key players of the ensuing immuneresponse. TGF-β and prostaglandin E2 (PGE2) are twoubiquitous immunomodulators, known to influence differentiationof DCs. Presence of TGF-β during differentiation of DCs with IL-4and 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 theprofile induced by TGF-β during differentiation of DCs. To this end,we incubated human monocytes for 5 days with IL-4 and GM-CSFalone (control DC) or with TGF-beta (T-DCs), with or without theaddition of PGE2 (10-7M) at the beginning of the culture.Compared to control DCs, T-DCs showed higher CD1a and decreasedCD14 expression, as well as enhanced LPS-induced IL-12production. Notably, LPS-induced expression of IL-10 was completelyabolished. However, simultaneous addition of PGE2 led toDCs showing a CD1a-CD14+ phenotype and unable to fully matureor 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), elicitedthe expansion of CD25+FoxP3+ T cells when cultured with allogeneicCD4+ lymphocytes (17.9% vs 8.0% in T-DCs). These resultsindicate that the presence of PGE2 can override TGF-β signalingand drive DCs towards a tolerogenic phenotype. Furthermore, wedemonstrated that inhibition of TGF-beta by PGE2 requires prostanoidreceptors EP2 and EP4, elevation of cyclinc AMP and PKAactivity.Taken together, these results suggest that potential TGF-β pro-inflammatoryactions on myeloid differentiation in the context of tumoror inflammatory microenvironment could be masked by the simultaneouspresence of PGE2.Keywords: inflammation, monocytes, dendritic cells, PGE2, TGF-β