PMID- 24029383
OWN - NLM
STAT- MEDLINE
DCOM- 20140902
LR  - 20211021
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Print)
IS  - 0891-5849 (Linking)
VI  - 65
DP  - 2013 Dec
TI  - Nrf2 is essential for the expression of lipocalin-prostaglandin D synthase 
      induced by prostaglandin D2.
PG  - 1134-1142
LID - S0891-5849(13)00595-9 [pii]
LID - 10.1016/j.freeradbiomed.2013.08.192 [doi]
AB  - 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.
CI  - (c) 2013 Elsevier Inc. All rights reserved.
FAU - Kim, Kyun Ha
AU  - Kim KH
AD  - Division of Applied Medicine, School of Korean Medicine, Pusan National 
      University, Yangsan 626-870, Korea.
FAU - Sadikot, Ruxana T
AU  - Sadikot RT
AD  - 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.
FAU - Xiao, Lei
AU  - Xiao L
AD  - Section of Pulmonary, Critical Care and Sleep Medicine, University of Illinois, 
      and Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
FAU - Christman, John W
AU  - Christman JW
AD  - Section of Pulmonary, Critical Care and Sleep Medicine, University of Illinois, 
      and Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
FAU - Freeman, Michael L
AU  - Freeman ML
AD  - Department of Radiation Oncology, Vanderbilt University School of Medicine, 
      Nashville, TN 37027, USA.
FAU - Chan, Jefferson Y
AU  - Chan JY
AD  - Department of Pathology and Laboratory Medicine, School of Medicine, University 
      of California at Irvine, Irvine, CA 92697, USA.
FAU - Oh, Yu-Kyoung
AU  - Oh YK
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul, Korea.
FAU - Blackwell, Timothy S
AU  - Blackwell TS
AD  - Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University 
      School of Medicine, Nashville, TN 37027, USA.
FAU - Joo, Myungsoo
AU  - Joo M
AD  - Division of Applied Medicine, School of Korean Medicine, Pusan National 
      University, Yangsan 626-870, Korea. Electronic address: mjoo@pusan.ac.kr.
LA  - eng
GR  - I01 BX001786/BX/BLRD VA/United States
GR  - R01 HL075557/HL/NHLBI NIH HHS/United States
GR  - R01 HL083218/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130909
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Lipocalins)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
RN  - EC 1.14.99.- (Ptgs2 protein, mouse)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 5.3.- (Intramolecular Oxidoreductases)
RN  - EC 5.3.99.2 (prostaglandin R2 D-isomerase)
RN  - RXY07S6CZ2 (Prostaglandin D2)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Base Sequence
MH  - Binding Sites/genetics
MH  - Cell Line
MH  - Cyclooxygenase 2/genetics
MH  - Intramolecular Oxidoreductases/*biosynthesis
MH  - Lipocalins/*biosynthesis
MH  - Lipopolysaccharides
MH  - Lung/metabolism/pathology
MH  - Macrophages/enzymology/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Neutrophil Infiltration/*immunology
MH  - Neutrophils/immunology
MH  - Pneumonia/genetics/*immunology
MH  - Promoter Regions, Genetic
MH  - Prostaglandin D2/*pharmacology
MH  - Protein Binding
MH  - RNA Interference
MH  - RNA, Small Interfering
MH  - Sequence Analysis, DNA
MH  - Toll-Like Receptor 4/genetics
PMC - PMC3972891
MID - NIHMS566667
OTO - NOTNLM
OT  - Free radicals
OT  - Gene expression
OT  - Lipocalin-prostaglandin D synthase
OT  - Lung inflammation
OT  - Nrf2
OT  - Prostaglandin D(2)
EDAT- 2013/09/14 06:00
MHDA- 2014/09/03 06:00
PMCR- 2014/04/02
CRDT- 2013/09/14 06:00
PHST- 2013/04/16 00:00 [received]
PHST- 2013/08/20 00:00 [revised]
PHST- 2013/08/30 00:00 [accepted]
PHST- 2013/09/14 06:00 [entrez]
PHST- 2013/09/14 06:00 [pubmed]
PHST- 2014/09/03 06:00 [medline]
PHST- 2014/04/02 00:00 [pmc-release]
AID - S0891-5849(13)00595-9 [pii]
AID - 10.1016/j.freeradbiomed.2013.08.192 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2013 Dec;65:1134-1142. doi: 
      10.1016/j.freeradbiomed.2013.08.192. Epub 2013 Sep 9.