Induction and function of lipocalin prostaglandin D synthase in host immunity.
Although mainly expressed in neuronal cells, lipocalin-type PGD synthase (L-PGDS) is detected in the macrophages infiltrated to atherosclerotic plaques. However, the regulation and significance of L-PGDS expression in macrophages are unknown. Here, we found that treatment of macrophages with bacterial endotoxin (LPS) or Pseudomonas induced L-PGDS expression. Epigenetic suppression of L-PGDS expression in macrophages blunted a majority of PGD(2) produced after LPS treatment. Chromatin immunoprecipitation assays show that L-PGDS induction was regulated positively by AP-1, but negatively by p53. L-PGDS expression was detected in whole lung and alveolar macrophages treated with LPS or Pseudomonas. L-PGDS overexpressing transgenic mice improved clearance of Pseudomonas from the lung compared with nontransgenic mice. Similarly, intratracheal instillation of PGD(2) enhanced removal of Pseudomonas from the lung in mice. In contrast, L-PGDS knockout mice were impaired in their ability to remove Pseudomonas from the lung. Together, our results identify induction of L-PGDS expression by inflammatory stimuli or bacterial infection, the regulatory mechanism of L-PGDS induction, and the protective role of L-PGDS expression in host immune response. Our study suggests a potential therapeutic usage of L-PGDS or PGD(2) against Pseudomonas pneumonia.
Joo
Myungsoo
M
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Myungsoo.Joo@vanderbilt.edu
Kwon
Minjae
M
Sadikot
Ruxana T
RT
Kingsley
Philip J
PJ
Marnett
Lawrence J
LJ
Blackwell
Timothy S
TS
Peebles
R Stokes
RS
Urade
Yoshihiro
Y
Christman
John W
JW
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology*; D054834:Lipocalins; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015230:Prostaglandin D2 / Q000494:pharmacology / Q000627:therapeutic use; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000276:immunology / Q000378:metabolism
D054834:Lipocalins; D008070:Lipopolysaccharides; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2