Mini-papers for Young Investigator’s Award Contestants’ Session (Van Arman Award) Mini-Paper 4
It is well known that prostaglandin (PG) E2 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 PGE2-mediated immunosuppression an enigma. Here we show that under strong TCR stimulation, PGE2 facilitates T helper-1 (TH-1) differentiation through activation of phosphatidylinositol-3-kinase (PI3K) by EP2 and EP4. The PGE2-EP4 signaling is also required for IL-23 production by activated dendritic cells (DCs), and the PGE2-EP2/EP4 signaling amplifies IL-23-mediated TH-17 cell expansion. Administration of an EP4-selective antagonist in vivo to mice subjected to experimental allergic encephalomyelitis (EAE) decreases accumulation of both TH-1 and TH-17 cells in regional lymph nodes, and suppresses the disease progression. These results suggest PGE2 promotes immune inflammation through TH-1 differentiation and TH-17 expansion and the EP4 antagonism is therapeutically useful for various immune diseases.