Prostaglandin E₂ 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 E₂ (PGE₂) 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 PGE₂ to regulate human Treg differentiation has not yet been reported. In the current study, we investigated the effects of PGE₂ 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 PGE₂ negatively influenced the percentage of Treg cells and Foxp3 mRNA expression. The regulatory effects of PGE₂ were associated with increased intracellular cAMP levels and PKA activity. EP2 receptors may mediate the inhibitory role of PGE₂, since PGE₂ 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). PGE₂ 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 PGE₂ can inhibit Treg differentiation mediated through the EP2-cAMP/PKA signaling pathway, and suggest novel immune-based therapies for use in RA treatment.