Original Contribution 2 PGD 2 and PGE 2 regulate gene expression of Prx 6 in primary macrophages via Nrf2

Abstract

Prostaglandin 26 Free radicals 27 Peroxiredoxin 6 (Prx 6) is a bifunctional enzyme with both glutathione peroxidase and acidic Ca 2+ -28 independent phospholipase A 2 activities. We have recently shown that exposure of murine bone marrow-29 derived macrophages to LPS and IFN-γ leads to induction of COX-2 expression and secretion of PGE 2 , up-30 regulating Prx 6 mRNA levels. This study was designed to investigate various prostaglandins (PGs) for their 31 ability to induce gene expression of Prx's, in particular Prx 6, and to determine the underlying regulatory 32 mechanisms. We provide evidence that both conventional and cyclopentenone PGs enhance Prx 6 mRNA 33 expression. Treatment with either activators or inhibitors of adenylate cyclase as well as cAMP analogs 34 indicated that Prx 6 gene expression is regulated by adenylate cyclase in response to PGD 2 or PGE 2 . 35 Furthermore, our study revealed that JAK2, PI3K, PKC, and p38 MAPK contribute to the PGD 2 -or PGE 2 -36 dependent Prx 6 induction. Using stimulated macrophages from Nrf2-deficient mice or activators of Nrf2 and 37 PPARγ, we found that Nrf2, but not PPARγ, is involved in the PG-dependent increase in Prx 6 mRNA 38 expression. In summary, our data suggest multiple signaling pathways of Prx 6 regulation by PGs and 39 identified Nrf2 as a critical player mediating transcriptional induction. 40 © 2011 Elsevier Inc. All rights reserved