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Induction and Function of Lipocalin Prostaglandin D Synthase in Host Immunity¹

Myungsoo Joo^2,*, Minjae Kwon^*, Ruxana T. Sadikot, Philip J. Kingsley, Lawrence J. Marnett, Timothy S. Blackwell^*, R. Stokes Peebles, Jr^*, Yoshihiro Urade and John W. Christman

^* Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; Section of Pulmonary, Critical Care and Sleep Medicine, University of Illinois and the Jesse Brown Veterans Affairs Medical Center, Chicago IL 60612; A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry and Chemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and the Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232; and Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan

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 PGD₂ 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 PGD₂ 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 PGD₂ against Pseudomonas pneumonia.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Department of Veterans Affairs and by National Institutes of Health Grants HL061419, HL075557, HL066196, AI054660, and HL069449.

² Address correspondence and reprint requests to Dr. Myungsoo Joo, Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, 1161 21st Avenue South, MCN B1222, Nashville, TN 37232-2650. E-mail address: Myungsoo.Joo{at}vanderbilt.edu

³ Abbreviations used in this paper: IKK, IB kinase; COX, cyclooxygenase; L-PGDS, lipocalin-type PGD synthase; H-PGDS, hemopoietic-type PGD synthase; BMDM, bone marrow-derived macrophage; KO, knockout; i.t., intratracheal; PA103, P. aeruginosa 103; BAL, bronchoalveolar lavage; siRNA, small interfering RNA; 15d-PGJ₂, 15-deoxy-^12,14-PGJ₂; ChIP, chromatin immunoprecipitation; RT, reverse transcription; moi, multiplicity of infection; DP, PGD₂ receptor; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells.