PGD2 and PGE2 regulate gene expression of Prx 6 in primary macrophages via Nrf2

Peroxiredoxin 6 (Prx 6) is a bifunctional enzyme with both glutathione peroxidase and acidic Ca2+-independent phospholipase A2 activities. We have recently shown that exposure of murine bone marrow-derived macrophages to LPS and IFN-γ leads to induction of COX-2 expression and secretion of PGE2, up-regulating Prx 6 mRNA levels. This study was designed to investigate various prostaglandins (PGs) for their ability to induce gene expression of Prxs, in particular Prx 6, and to determine the underlying regulatory mechanisms. We provide evidence that both conventional and cyclopentenone PGs enhance Prx 6 mRNA expression. Treatment with either activators or inhibitors of adenylate cyclase as well as cAMP analogs indicated that Prx 6 gene expression is regulated by adenylate cyclase in response to PGD2 or PGE2. Furthermore, our study revealed that JAK2, PI3K, PKC, and p38 MAPK contribute to the PGD2- or PGE2-dependent Prx 6 induction. Using stimulated macrophages from Nrf2-deficient mice or activators of Nrf2 and PPARγ, we found that Nrf2, but not PPARγ, is involved in the PG-dependent increase in Prx 6 mRNA expression. In summary, our data suggest multiple signaling pathways of Prx 6 regulation by PGs and identified Nrf2 as a critical player mediating transcriptional induction.