Nrf2 is essential for the expression of lipocalin-prostaglandin D synthase induced by prostaglandin D-2

作者：Kim Kyun Ha; Sadikot Ruxana T; Xiao Lei; Christman John W; Freeman Michael L; Chan Jefferson Y; Oh Yu Kyoung; Blackwell Timothy S; Joo Myungsoo^*

来源：Free Radical Biology and Medicine, 2013, 65: 1134-1142.

DOI：10.1016/j.freeradbiomed.2013.08.192

• Nrf2
• Lung inflammation
• Lipocalin-prostaglandin D synthase
• Prostaglandin D-2
• Gene expression
• Free radicals

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 D-2 (PGD(2)) induced L-PGDS expression in bone-marrow-derived macrophages (BMDMs), suggesting a positive feedback loop between L-PGDS expression and PGD(2). Unlike lipopolysaccharide (LPS)-induced L-PGDS expression, PGD(2)-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 PGD(2). 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 PGD(2) 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 PGD(2), induced L-PGDS expression, resulting in decreased inflammation. We suggest that the positive feedback induction of L-PGDS by PGD(2) is part of the mechanism by which Nrf2 regulates inflammation.

• 出版日期2013-12