title: Nrf2 is essential for the expression of lipocalin-prostaglandin D synthase induced by prostaglandin D2.
abstract: Nrf2 is a transcription factor that protects against inflammatory diseases, but the underlying mechanism of this effect remains unclear. Here, we report that Nrf2 uses lipocalin-prostaglandin D synthase (L-PGDS) as a mechanism for suppressing inflammation. Exogenously added prostaglandin D2 (PGD2) induced L-PGDS expression in bone-marrow-derived macrophages (BMDMs), suggesting a positive feedback loop between L-PGDS expression and PGD2. Unlike lipopolysaccharide (LPS)-induced L-PGDS expression, PGD2-mediated expression was independent of MAPK, PU.1, or TLR4. Sequence analysis located a putative Nrf2 binding site in the murine L-PGDS promoter, to which Nrf2 bound when treated with PGD2. Chemical activation, or overexpression, of Nrf2 was sufficient to induce L-PGDS expression in macrophages, BMDMs, or lungs of Nrf2-knockout (KO) mice, but treatment with PGD2 failed to do so, suggesting a pivotal role for Nrf2 in the expression of L-PGDS. Consistent with this, expression of Nrf2 in the lungs of Nrf2-KO mice was sufficient to induce the expression of L-PGDS and to reduce neutrophilic lung inflammation elicited by LPS. Furthermore, expression of L-PGDS in mouse lungs decreased neutrophilic infiltration, ameliorating lung inflammation in mice. Together, our results show that Nrf2, activated by PGD2, induced L-PGDS expression, resulting in decreased inflammation. We suggest that the positive feedback induction of L-PGDS by PGD2 is part of the mechanism by which Nrf2 regulates inflammation.
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan 626-870, Korea.
authors.forename: Kyun Ha
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Division of Allergy, Pulmonary, Critical Care and Sleep Medicine, College of Medicine, University of Florida, and Malcom Randall Veterans Affairs Medical Center, Gainesville, FL 32610, USA.
authors.forename: Ruxana T
authors.initials: RT
authors.lastname: Sadikot
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, University of Illinois, and Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, University of Illinois, and Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
authors.affiliation: Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN 37027, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Freeman
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of California at Irvine, Irvine, CA 92697, USA.
authors.forename: Jefferson Y
authors.initials: JY
authors.lastname: Chan
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Oh
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37027, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan 626-870, Korea. Electronic address: mjoo@pusan.ac.kr.
authors.forename: Myungsoo
authors.initials: M
authors.lastname: Joo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis*; D054834:Lipocalins / Q000096:biosynthesis*; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000235:genetics / Q000276:immunology*; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D017422:Sequence Analysis, DNA; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D054834:Lipocalins; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D034741:RNA, Small Interfering; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2
keywords: Free radicals; Gene expression; Lipocalin–prostaglandin D synthase; Lung inflammation; Nrf2; Prostaglandin D(2)
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