Published ahead of print on June 21, 2007, doi:10.1165/rcmb.2007-0153OC
American Journal of Respiratory Cell and Molecular Biology. Vol. 37, pp. 562-570, 2007
© 2007 American Thoracic Society DOI: 10.1165/rcmb.2007-0153OC
Prostaglandin E2 Suppresses Bacterial Killing in Alveolar Macrophages by Inhibiting NADPH Oxidase
Carlos H. Serezani1,
Jooho Chung1,
Megan N. Ballinger1,
Bethany B. Moore1,
David M. Aronoff2 and
Marc Peters-Golden1
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 (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 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 Gs-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.
|
This article has been cited by other articles:

|
 |

|
 |
 
N. Cobbe, K. M. Marshall, S. G. Rao, C.-W. Chang, F. Di Cara, E. Duca, S. Vass, A. Kassan, and M. M. S. Heck
The conserved metalloprotease invadolysin localizes to the surface of lipid droplets
J. Cell Sci.,
September 15, 2009;
122(18):
3414 - 3423.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. M. Aronoff, C. Lewis, C. H. Serezani, K. A. Eaton, D. Goel, J. C. Phipps, M. Peters-Golden, and P. Mancuso
E-Prostanoid 3 Receptor Deletion Improves Pulmonary Host Defense and Protects Mice from Death in Severe Streptococcus pneumoniae Infection
J. Immunol.,
August 15, 2009;
183(4):
2642 - 2649.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. A. Sorgi, A. Secatto, C. Fontanari, W. M. Turato, C. Belanger, A. I. de Medeiros, S. Kashima, S. Marleau, D. T. Covas, P. T. Bozza, et al.
Histoplasma capsulatum Cell Wall {beta}-Glucan Induces Lipid Body Formation through CD18, TLR2, and Dectin-1 Receptors: Correlation with Leukotriene B4 Generation and Role in HIV-1 Infection
J. Immunol.,
April 1, 2009;
182(7):
4025 - 4035.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K. S. Farley, L. Wang, and S. Mehta
Septic pulmonary microvascular endothelial cell injury: role of alveolar macrophage NADPH oxidase
Am J Physiol Lung Cell Mol Physiol,
March 1, 2009;
296(3):
L480 - L488.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. I. Medeiros, C. H. Serezani, S. P. Lee, and M. Peters-Golden
Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling
J. Exp. Med.,
January 16, 2009;
206(1):
61 - 68.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. P. Lee, C. H. Serezani, A. I. Medeiros, M. N. Ballinger, and M. Peters-Golden
Crosstalk between Prostaglandin E2 and Leukotriene B4 Regulates Phagocytosis in Alveolar Macrophages via Combinatorial Effects on Cyclic AMP
J. Immunol.,
January 1, 2009;
182(1):
530 - 537.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. Chung, C. H. Serezani, S. K. Huang, J. N. H. Stern, D. B. Keskin, R. Jagirdar, T. G. Brock, D. M. Aronoff, and M. Peters-Golden
Rap1 Activation Is Required for Fc{gamma} Receptor-Dependent Phagocytosis
J. Immunol.,
October 15, 2008;
181(8):
5501 - 5509.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. K. Huang, S. H. Wettlaufer, J. Chung, and M. Peters-Golden
Prostaglandin E2 Inhibits Specific Lung Fibroblast Functions via Selective Actions of PKA and Epac-1
Am. J. Respir. Cell Mol. Biol.,
October 1, 2008;
39(4):
482 - 489.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. H. Serezani, M. N. Ballinger, D. M. Aronoff, and M. Peters-Golden
Cyclic AMP: Master Regulator of Innate Immune Cell Function
Am. J. Respir. Cell Mol. Biol.,
August 1, 2008;
39(2):
127 - 132.
[Abstract]
[Full Text]
[PDF]
|
 |
|
Copyright © 2007 American Thoracic Society.
|
|
|