Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2).
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 J(2) (15d-PGJ(2)), it was observed that macrophages from pleural lavage accumulate 15d-PGJ(2). 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-PGJ(2) accumulation and PrxI expression. Administration of 15d-PGJ(2) 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-PGJ(2) by orchestrating the recruitment of inflammatory cells and regulating the gene expression within those cells.
Itoh
Ken
K
ERATO Environmental Response Project, University of Tsukuba, Tsukuba 305-8577, Japan.
Mochizuki
Mie
M
Ishii
Yukio
Y
Ishii
Tetsuro
T
Shibata
Takahiro
T
Kawamoto
Yoshiyuki
Y
Kelly
Vincent
V
Sekizawa
Kiyohisa
K
Uchida
Koji
K
Yamamoto
Masayuki
M
D000818:Animals; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000378:metabolism*; D022781:Hepatocytes; D007249:Inflammation / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2; D010537:Peritoneum / Q000378:metabolism; D010998:Pleurisy / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015534:Trans-Activators; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015230:Prostaglandin D2