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

Kyun Ha Kim, Ruxana T. Sadikot, Lei Xiao, John W. Christman, Michael L. Freeman, Jefferson Y. Chan, Yu Kyoung Oh, Timothy S. Blackwell, Myungsoo Joo

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1134-1142
Number of pages9
JournalFree Radical Biology and Medicine
Volume65
DOIs
StatePublished - 2013
Externally publishedYes

Keywords

  • Free radicals
  • Gene expression
  • Lipocalin-prostaglandin D synthase
  • Lung inflammation
  • Nrf2

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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