A Novel Nrf2-Mediated Antioxidative and Antiinflammatory Mechanism through Ferroportin 1 Induction : A Potential Cytoprotective Mechanism against Ischemia-Reperfusion Injuries

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The long-term function of a graft after transplantation is dependent upon ischemia-reperfusion （I/R） injury, which represents the most important alloantigen-independent damage processes during transplantation. Basic leucine zipper（ b-Zip） transcription factor NF-E2-related factor 2（ Nrf2） is protective against I/R injury by promoting antioxidative and anti-inflammatory mechanisms via up-regulation of antioxidant-responsive element （ARE）-regulated genes such as heme oxygenase 1 and γ-glutamylcysteine ligase. We previously demonstrated that macrophage Nrf2 plays an important role in an elastase-induced acute lung injury model. To further clarify the mechanisms that act downstream of Nrf2, we performed microarray analysis in the RAW264.7 murine macrophage cell line using endogenous electrophilic prostaglandin 15-deoxy-Δ12,14-prostagrandin J2 （15d-PGJ2）. As a result, we identified ferroportin 1 （Fpn1） as a novel Nrf2 target gene. Fpn1 is the sole iron exporter in mammals and regulates iron homeostasis. On the other hand, free intracellular iron is detrimental to cells by enhancing both inflammation and Fenton reaction-mediated oxidative stress. We demonstrated that Nrf2 activation by several electrophilic compounds commonly result in the up-regulation of Fpn1 mRNA in bone marrow-derived and peritoneal macrophages obtained from wild-type, but not from Nrf2 knockout mice. Furthermore, Nrf2 activation enhances iron release from the murine macrophage cell line J774.1. It is previously reported that LPS suppresses Fpn1 mRNA expression, which leads to iron retention in monocytes and macrophages. We showed that while LPS suppress Fpn1 mRNA expression in human macrophages, Nrf2 activation restores the expression of Fpn1. Thus, we propose that iron-metabolism regulation may be an important factor of the Nrf2-mediated cytoprotective mechanism.

弘前医学. 64(Suppl.), 2013, p.S74-S80

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  • 弘前医学

    弘前医学 64 (Supplement), S74-S80, 2013-04-02

    弘前大学大学院医学研究科・弘前医学会

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