Prostaglandins D2 and E2 have opposite effects on alveolar macrophages infected with Histoplasma capsulatum

Prostaglandin E2 (PGE(2)) suppresses macrophage effector mechanisms; however, little is known about the function of PGD(2) in infected alveolar macrophages (AMs). Using serum-opsonized Histoplasma capsulatum (Ops-H. capsulatum) in vitro, we demonstrated that AMs produced PGE(2) and PGD(2) in a time-dependent manner, with PGE(2) levels exceeding those of PGD(2) by 48 h postinfection. Comparison of the effects of both exogenous PGs on AMs revealed that PGD(2) increased phagocytosis and killing through the chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes receptor, whereas PGE(2) had opposite effects, through E prostanoid (EP) receptor 2 (EP2)/EP4-dependent mechanisms. Moreover, PGD(2) inhibited phospholipase C-gamma (PLC-gamma) phosphorylation, reduced IL-10 production, and increased leukotriene B4 receptor expression. In contrast, exogenous PGE(2) treatment reduced PLC-gamma phosphorylation, p38 and nuclear factor kappa B activation, TNF-alpha, H2O2, and leukotriene B4, but increased IL-1 beta. production. Using specific compounds to inhibit the synthesis of each PG in vitro and in vivo, we found that endogenous PGD(2) contributed to fungicidal mechanisms and controlled inflammation, whereas endogenous PGE(2) decreased phagocytosis and killing of the fungus and induced inflammation. These findings demonstrate that, although PGD(2) acts as an immunostimulatory mediator to control H. capsulatum infection, PGE(2) has immunosuppressive effects, and the balance between these two PGs may limit collateral immune damage at the expense of microbial containment.