Abstract
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.
Publication types
-
Comparative Study
-
Research Support, N.I.H., Extramural
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Atherosclerosis / genetics
-
Atherosclerosis / immunology
-
Atherosclerosis / pathology
-
Cell Line
-
Epigenesis, Genetic / drug effects
-
Epigenesis, Genetic / genetics
-
Epigenesis, Genetic / immunology
-
Gene Expression Regulation, Enzymologic / drug effects
-
Gene Expression Regulation, Enzymologic / genetics
-
Gene Expression Regulation, Enzymologic / immunology*
-
Immunity, Innate* / genetics
-
Intramolecular Oxidoreductases / biosynthesis
-
Intramolecular Oxidoreductases / deficiency
-
Intramolecular Oxidoreductases / immunology*
-
Lipocalins
-
Lipopolysaccharides / immunology
-
Lipopolysaccharides / pharmacology
-
Macrophages / enzymology
-
Macrophages / immunology*
-
Macrophages / pathology
-
Mice
-
Mice, Knockout
-
Pneumonia, Bacterial / drug therapy
-
Pneumonia, Bacterial / enzymology
-
Pneumonia, Bacterial / genetics
-
Pneumonia, Bacterial / immunology*
-
Pneumonia, Bacterial / pathology
-
Prostaglandin D2 / pharmacology
-
Prostaglandin D2 / therapeutic use
-
Pseudomonas Infections / drug therapy
-
Pseudomonas Infections / enzymology
-
Pseudomonas Infections / genetics
-
Pseudomonas Infections / immunology*
-
Pseudomonas aeruginosa / immunology
-
Transcription Factor AP-1 / immunology
-
Transcription Factor AP-1 / metabolism
-
Tumor Suppressor Protein p53 / immunology
-
Tumor Suppressor Protein p53 / metabolism
Substances
-
Lipocalins
-
Lipopolysaccharides
-
Transcription Factor AP-1
-
Tumor Suppressor Protein p53
-
Intramolecular Oxidoreductases
-
prostaglandin R2 D-isomerase
-
Prostaglandin D2