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Molecular and Cellular Biology, January 2004, p. 36-45, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.36-45.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Ken Itoh,^1,2, Mie Mochizuki,^3, Yukio Ishii,³ Tetsuro Ishii,⁴ Takahiro Shibata,⁵ Yoshiyuki Kawamoto,⁵ Vincent Kelly,^1,2 Kiyohisa Sekizawa,³ Koji Uchida,⁴ and Masayuki Yamamoto^1,2*

ERATO Environmental Response Project,¹ Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance,² Institute of Clinical Medicines,³ Institute of Social Medicines, University of Tsukuba, Tsukuba 305-8577,⁴ Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan⁵

Received 25 April 2003/ Returned for modification 17 July 2003/ Accepted 26 September 2003

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-^12,14-prostaglandin J₂ (15d-PGJ₂), it was observed that macrophages from pleural lavage accumulate 15d-PGJ₂. We show that in mouse peritoneal macrophages 15d-PGJ₂ 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.

K.I. and M.M. contributed equally to this work.

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