Crosstalk between prostaglandin E2 and leukotriene B4 regulates phagocytosis in alveolar macrophages via combinatorial effects on cyclic AMP.
Eicosanoid lipid mediators, including prostaglandin E(2) (PGE(2)) and leukotrienes (LTs) B(4) and D(4), are produced in abundance in the infected lung. We have previously demonstrated that individually, PGE(2) 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 Fc gammaR-mediated phagocytosis when they are present in combination. Consistent with their individual actions, both LTB(4) and LTD(4) opposed the suppressive effect of PGE(2) on phagocytosis, but only LTB(4) did so by mitigating the stimulatory effect of PGE(2) 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 G alpha i inhibitor pertussis toxin. Of two downstream cAMP effectors, protein kinase A and exchange protein activated by cAMP, the ability of PGE(2) to activate the latter but not the former was abrogated by both LTs B(4) and D(4). Taken together, our results indicate that both classes of LTs oppose the immune suppressive actions of PGE(2), with the stimulatory actions of LTB(4) reflecting combinatorial modulation of intracellular cAMP and those of LTD(4) being cAMP independent.
Lee
Sang Pyo
SP
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
Serezani
Carlos H
CH
Medeiros
Alexandra I
AI
Ballinger
Megan N
MN
Peters-Golden
Marc
M
D000818:Animals; D002450:Cell Communication / Q000276:immunology*; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D000242:Cyclic AMP / Q000378:metabolism* / Q000502:physiology; D015232:Dinoprostone / Q000378:metabolism / Q000502:physiology*; D004357:Drug Synergism; D005260:Female; D007975:Leukotriene B4 / Q000378:metabolism / Q000502:physiology*; D017998:Leukotriene D4 / Q000502:physiology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology*; D051381:Rats; D017208:Rats, Wistar; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D017452:Receptors, IgG; D007975:Leukotriene B4; D017998:Leukotriene D4; D000242:Cyclic AMP; D015232:Dinoprostone