Published ahead of print on June 21, 2007, doi:10.1165/rcmb.2007-0153OC Am. J. Respir. Cell Mol. Biol., Volume 37, Number 5, November 2007, 562-570 A more recent version of this article appeared on November 1, 2007
Submitted on April 27, 2007 Prostaglandin E2 Suppresses Bacterial Killing in Alveolar Macrophages by Inhibiting NADPH OxidaseCarlos H Serezani1,1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Health Systems, Ann Arbor, MI, United States, 2 Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Health Systems, Ann Arbor, MI, USA * To whom correspondence should be addressed. 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), though 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 Gs-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 NADPH oxidase component p47phox to the phagosomal membrane. We conclude that PGE2 suppresses the microbicidal activity of AMs through the Gs-coupled EP2/EP4 receptors, with increased cAMP inhibiting the assembly and activation of p47phox.
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