Transcription Factor Nrf2 Regulates Inflammation by Mediating the Effect of 15-Deoxy-Δ12,14-Prostaglandin J2

Ken Itoh, Mie Mochizuki, Yukio Ishii, Tetsuro Ishii, Takahiro Shibata, Yoshiyuki Kawamoto, Vincent Kelly, Kiyohisa Sekizawa, Koji Uchida, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

321 Citations (Scopus)

Abstract

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-Δ12,14-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.

Original languageEnglish
Pages (from-to)36-45
Number of pages10
JournalMolecular and cellular biology
Volume24
Issue number1
DOIs
Publication statusPublished - 2004 Jan

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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