Receptors for prostaglandin E-2 that regulate cellular immune responses inthe mouse

Production of prostaglandin E-2 (PGE(2)) is enhanced during inflammation, a nd this Lipid mediator can dramatically modulate immune responses. There ar e four receptors for PGE(2) (EP1-EP4) with unique patterns of expression an d different coupling to intracellular signaling pathways. To identify the E P receptors that regulate cellular immune responses, we used mouse lines in which the genes encoding each of the four EP receptors were disrupted by g ene targeting. Using the mixed lymphocyte response (MLR) as a model cellula r immune response, we confirmed that PGE(2) has potent antiproliferative ef fects on wild-type responder cells. The absence of either the EP1 or EP3 re ceptors did not alter the inhibitory response to PGE(2) in the MLR. In cont rast, when responder cells lacked the EP2 receptor, PGE(2) had little effec t on proliferation. Modest resistance to PGE(2) was also observed in EP4(-/ -) responder cells. Reconstitution experiments suggest that EP2 receptors p rimarily inhibit the MLR through direct actions on T cells. Furthermore, PG E(2) modulates macrophage function by activating the EN receptor and thereb y inhibiting cytokine release. Thus, PGE(2) regulates cellular immune respo nses through distinct EP receptors on different immune cell populations: EP 2 receptors directly inhibit T cell proliferation while EP2 and EP4 recepto rs regulate antigen presenting cells functions.