Transcription Factor Nrf2 Regulates Inflammation by Mediating the Effect of 15-Deoxy-Δ^12,14-Prostaglandin J₂

Activated macrophages express high levels of Nrf2, a transcription factor that positively regulates the gene expression of antioxidant and detoxication enzymes. In this study, we examined how Nrf2 contributes to the anti-inflammatory process. As a model system of acute inflammation, we administered carrageenan to induce pleurisy and found that in Nrf2-deficient mice, tissue invasion by neutrophils persisted during inflammation and the recruitment of macrophages was delayed. Using an antibody against 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ ₂), it was observed that macrophages from pleural lavage accumulate 15d-PGJ₂. We show that in mouse peritoneal macrophages 15d-PGJ ₂ can activate Nrf2 by forming adducts with Keap1, resulting in an Nrf2-dependent induction of heme oxygenase 1 and peroxiredoxin I (PrxI) gene expression. Administration of the cyclooxygenase 2 inhibitor NS-398 to mice with carrageenan-induced pleurisy caused persistence of neutrophil recruitment and, in macrophages, attenuated the 15d-PGJ₂ accumulation and PrxI expression. Administration of 15d-PGJ₂ into the pleural space of NS-398-treated wild-type mice largely counteracted both the decrease in PrxI and persistence of neutrophil recruitment. In contrast, these changes did not occur in the Nrf2-deficient mice. These results demonstrate that Nrf2 regulates the inflammation process downstream of 15d-PGJ₂ by orchestrating the recruitment of inflammatory cells and regulating the gene expression within those cells.