Effect of prostaglandin E2 on intercellular adhesion molecule-1 and B7 expression in mixed lymphocyte reaction

The elevation of plasma interleukin (IL)-18 levels and the expression of intercellular adhesion molecule (ICAM)-1 and B7 on monocytes are involved in acute rejection. Prostaglandin (PG) E2 suppresses the rejection in animal transplantation models; however, little is known about its action mechanism. We examined the effect of PGE2 on the expression of ICAM-1 and B7 in the human mixed leukocyte reaction (MLR) in the presence or absence of IL-18. We measured the expression of ICAM-1, B7.1, and B7.2 on human monocytes by flow cytometry and determined the associated production of interferon-gamma and IL-12 by enzyme-linked immunosorbent assay. The modulatory effects of PGE2 and the relevant PGE2 receptor subtypes were characterized pharmacologically. PGE2 inhibited the expression of ICAM-1, B7.1, and B7.2 on monocytes in MLR in a concentration-dependent manner. Whereas IL-18 significantly induced the expression of ICAM-1, B7.1, and B7.2 on monocytes in MLR and the production of interferon-gamma and IL-12, PGE2 inhibited these IL-18-initiated enhancements. The effects of PGE2 were mimicked by selective EP2 and EP4 agonists, but not by EP1 and EP3 agonists. PGE2 strongly inhibited MLR with respect to the expression of ICAM-1, B7.1, and B7.2 via the EP2 and EP4 receptors, irrespective of the presence or absence of IL-18. In the previous study, histamine inhibited ICAM-1 expression in the presence of IL-18 but had no effect in the absence of IL-18. These results indicate that the inhibitory effect of PGE2 may be more general and stronger than that of histamine and may play an important role in future immunosuppressive strategies.