Crosstalk between Prostaglandin E2 and Leukotriene B4 Regulates Phagocytosis in Alveolar Macrophages via Combinatorial Effects on Cyclic AMP

Abstract

Eicosanoid lipid mediators, including prostaglandin E2 (PGE2) and leukotrienes (LTs) B4 and D4, are produced in abundance in the infected lung. We have previously demonstrated that individually, PGE2 suppresses while both classes of LTs augment alveolar macrophage (AM) innate immune functions. In this study, we sought to more appropriately model the milieu at a site of infection by studying the in vitro effects of these lipid mediators on FcγR-mediated phagocytosis when they are present in combination. Consistent with their individual actions, both LTB4 and LTD4 opposed the suppressive effect of PGE2 on phagocytosis, but only LTB4 did so by mitigating the stimulatory effect of PGE2 on intracellular cAMP production. Unexpectedly, we observed that IgG-opsonized targets themselves elicited a dose-dependent reduction in intracellular cAMP in AMs, but this was not observed in peritoneal macrophages or elicited peritoneal neutrophils; this effect in AMs was completely abolished by treatment with the LT synthesis inhibitor AA861, the BLT receptor 1 antagonist CP 105,696, and the Gαi inhibitor pertussis toxin. Of two downstream cAMP effectors, protein kinase A and exchange protein activated by cAMP, the ability of PGE2 to activate the latter but not the former was abrogated by both LTs B4 and D4. Taken together, our results indicate that both classes of LTs oppose the immune suppressive actions of PGE2, with the stimulatory actions of LTB4 reflecting combinatorial modulation of intracellular cAMP and those of LTD4 being cAMP independent.