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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-{Delta}12,14-Prostaglandin J2

Ken Itoh,1,2,{dagger} Mie Mochizuki,3,{dagger} Yukio Ishii,3 Tetsuro Ishii,4 Takahiro Shibata,5 Yoshiyuki Kawamoto,5 Vincent Kelly,1,2 Kiyohisa Sekizawa,3 Koji Uchida,4 and Masayuki Yamamoto1,2*

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-{Delta}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.

* Corresponding author. Mailing address: Center for TARA, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan. Phone: 81-298-53-6158. Fax: 81-298-53-7318. E-mail: masi{at}tara.tsukuba.ac.jp.

{dagger} K.I. and M.M. contributed equally to this work.

Molecular and Cellular Biology, January 2004, p. 36-45, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.36-45.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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