Prostaglandin E Receptor Subtypes EP2 and EP4 Promote T H 1 Cell Differentiation and T H 17 Cell Expansion Through Different Signaling Modules

It is well known that prostaglandin (PG) E 2 exerts T cell suppression in vitro through elevating cAMP by its receptors, EP2 and EP4. However, such an action is rarely detected in vivo , leaving PGE 2 -mediated immunosuppression an enigma. Here we show that under strong TCR stimulation, PGE 2 facilitates T helper-1 (T H -1) differentiation through activation of phosphatidylinositol-3-kinase (PI3K) by EP2 and EP4. The PGE 2 -EP4 signaling is also required for IL-23 production by activated dendritic cells (DCs), and the PGE2-EP2/EP4 signaling amplifies IL-23-mediated T H -17 cell expansion. Administration of an EP4-selective antagonist in vivo to mice subjected to experimental allergic encephalomyelitis (EAE) decreases accumulation of both T H -1 and T H -17 cells in regional lymph nodes, and suppresses the disease progression. These results suggest PGE 2 promotes immune inflammation through T H -1 differentiation and T H -17 expansion and the EP4 antagonism is therapeutically useful for various immune diseases.