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Prostaglandin E₂ Suppresses Bacterial Killing in Alveolar Macrophages by Inhibiting NADPH Oxidase

¹ Division of Pulmonary and Critical Care Medicine; and ² Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Health Systems, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Marc Peters-Golden, M.D., 6301 MSRB III, Box 0642; 1150 W. Medical Center Drive, University of Michigan Health System, Ann Arbor, MI 48109-0642. E-mail: petersm{at}umich.edu

Prostaglandin E₂ (PGE₂) is a potent lipid mediator that effects changes in cell functions through ligation of four distinct G protein–coupled E prostanoid (EP) receptors (EP1–EP4). PGE₂ inhibits bacterial killing and reactive oxygen intermediate (ROI) production by alveolar macrophages (AMs), although little is known about the operative molecular mechanisms. The aims of this study were to evaluate the molecular mechanisms and the specific EP receptors through which PGE₂ inhibits killing of Klebsiella pneumoniae by AMs. The treatment of AMs with PGE₂ suppressed the killing of K. pneumoniae, and this effect was blocked by an adenylyl cyclase inhibitor and mimicked by agonists for the stimulatory G protein (G_s)-coupled EP2 and EP4 receptors. Conversely, microbicidal activity was augmented by pretreatment with the cyclooxygenase inhibitor, indomethacin, and antagonists of EP2 and EP4. Similar results were found when ROI production was examined. PGE₂ inhibition of killing and ROI generation was associated with its activation of the cAMP effectors, protein kinase A and exchange protein directly activated by cAMP-1, as well as attenuation of the phosphorylation and translocation of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase component, p47phox, to the phagosomal membrane. We conclude that PGE₂ suppresses the microbicidal activity of AMs through the G_s-coupled EP2/EP4 receptors, with increased cAMP inhibiting the assembly and activation of p47phox.

Key Words: bacterial killing • lipid mediators • macrophage • phagosome • prostaglandin E₂ • NADPH

CLINICAL RELEVANCE This study identifies an important role of prostaglandin E2 acting through E prostanoid (EP) 2 and EP4 receptors to limit alveolar macrophage microbicidal activity, provides new insights into the regulation of innate immune cells, and suggests potential strategies for immunostimulant therapeutics.