Prostaglandin E restrains human Treg cell differentiation via E prostanoid receptor 2-protein kinase A signaling.

Regulatory T cells (Treg cells) belong to a class of immunosuppressive cells that control the pathological changes of autoimmunity and inflammation. Prostaglandin E (PGE) is a potent lipid mediator of immune inflammation including rheumatoid arthritis (RA) that exerts its effects via four subtypes of G-protein-coupled receptors (EP1-4). The ability of PGE to regulate human Treg differentiation has not yet been reported. In the current study, we investigated the effects of PGE on the differentiation of naïve T cells from healthy and RA patients into Treg cells and the intracellular signaling involved in this process in vitro. Our data indicate that PGE negatively influenced the percentage of Treg cells and Foxp3 mRNA expression. The regulatory effects of PGE were associated with increased intracellular cAMP levels and PKA activity. EP2 receptors may mediate the inhibitory role of PGE, since PGE actions were mimicked by EP2 agonist (Butaprost) and cAMP agonist (Sp-8-CPT-cAMPS) but were reversed by an EP2 antagonist (PF-04418948) and a PKA inhibitor (H-89). PGE negatively modulated the expression of cytotoxic T lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), as well as the production of interleukin (IL)-10 by Treg cells via EP2 receptors and cAMP/PKA signaling. All these findings indicate that PGE can inhibit Treg differentiation mediated through the EP2-cAMP/PKA signaling pathway, and suggest novel immune-based therapies for use in RA treatment.