Production of prostaglandin E2 (PGE2) is enhanced during inflammation, and this lipid mediator can dramatically modulate immune responses. There are four receptors for PGE2 (EP1-EP4) with unique patterns of expression and different coupling to intracellular signaling pathways. To identify the EP receptors that regulate cellular immune responses, we used mouse lines in which the genes encoding each of the four EP receptors were disrupted by gene targeting. Using the mixed lymphocyte response (MLR) as a model cellular immune response, we confirmed that PGE2 has potent antiproliferative effects on wild-type responder cells. The absence of either the EP1 or EP3 receptors did not alter the inhibitory response to PGE2 in the MLR. In contrast, when responder cells lacked the EP2 receptor, PGE2 had little effect on proliferation. Modest resistance to PGE2 was also observed in EP4-/- responder cells. Reconstitution experiments suggest that EP2 receptors primarily inhibit the MLR through direct actions on T cells. Furthermore, PGE2 modulates macrophage function by activating the EP4 receptor and thereby inhibiting cytokine release. Thus, PGE2 regulates cellular immune responses through distinct EP receptors on different immune cell populations: EP2 receptors directly inhibit T cell proliferation while EP2 and EP4 receptors regulate antigen presenting cells functions.
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