Nrf2 is essential for the expression of lipocalin-prostaglandin D synthase induced by prostaglandin D2.

Kim KH, Sadikot RT, Xiao L, Christman JW, Freeman ML, Chan JY, Oh YK, Blackwell TS, Joo M
Free Radic Biol Med. 2013 65: 1134-1142

PMID: 24029383 · PMCID: PMC3972891 · DOI:10.1016/j.freeradbiomed.2013.08.192

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.

© 2013 Elsevier Inc. All rights reserved.

MeSH Terms (25)

Amino Acid Sequence Animals Base Sequence Binding Sites Cell Line Cyclooxygenase 2 Intramolecular Oxidoreductases Lipocalins Lipopolysaccharides Lung Macrophages Mice Mice, Inbred C57BL Mice, Knockout Neutrophil Infiltration Neutrophils NF-E2-Related Factor 2 Pneumonia Promoter Regions, Genetic Prostaglandin D2 Protein Binding RNA, Small Interfering RNA Interference Sequence Analysis, DNA Toll-Like Receptor 4

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