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Crosstalk between Prostaglandin E₂ and Leukotriene B₄ Regulates Phagocytosis in Alveolar Macrophages via Combinatorial Effects on Cyclic AMP¹

Sang Pyo Lee^*,, Carlos H. Serezani^*, Alexandra I. Medeiros^*, Megan N. Ballinger^* and Marc Peters-Golden^2,*

^* Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Health System, Ann Arbor, MI 48109; and Gachon University Gil Hospital, Incheon, South Korea

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 FcR-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 Gi 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL058897 (to M.P.G.), an American Lung Association senior research training grant RT-78960-N (to C.H.S.), a Hartwell Foundation fellowship (to M.N.B.), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-201061/2007-4; to A.I.M.).

² Address correspondence and reprint requests to Dr. Marc Peters-Golden, 6301 MSRB III; 1150 W. Medical Center Drive, University of Michigan Health System, Ann Arbor, MI 48109-5642. E-mail address: petersm{at}umich.edu

³ Abbreviations used in this paper: AM, alveolar macrophage; COX, cyclooxygenase; 5-LO, 5-lipoxygenase; PGE₂, prostaglandin E₂; LT, leukotriene; EP, E prostanoid; PKA, protein kinase A; VASP, vasodilator-stimulated phosphoprotein; Epac-1, exchange protein activated by cAMP-1; BLT1, type 1 B LT receptor; cysLT1, type 1 cysLT receptor; PTX, pertussis toxin; PM, peritoneal macrophage; PMN, polymorphonuclear leukocyte.