Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element

作者：Elisabeth Abidemi Balogun, Martha Hoque, Pengfei Gong, Erin Killeen, Colin J. Green, Roberta Foresti, Jawed Alam, Roberto Motterlini · 发表于：Biochemical Journal · 年份：2003 · DOI：10.1042/bj20021619 · 被引用次数：1035 · 研究领域：Heme Oxygenase-1 and Carbon Monoxide、Genomics, phytochemicals, and oxidative stress、Alcohol Consumption and Health Effects

The transcription factor Nrf2, which normally exists in an inactive state as a consequence of binding to a cytoskeleton-associated protein Keap1, can be activated by redox-dependent stimuli. Alteration of the Nrf2-Keap1 interaction enables Nrf2 to translocate to the nucleus, bind to the antioxidant-responsive element (ARE) and initiate the transcription of genes coding for detoxifying enzymes and cytoprotective proteins. This response is also triggered by a class of electrophilic compounds including polyphenols and plant-derived constituents. Recently, the natural antioxidants curcumin and caffeic acid phenethyl ester (CAPE) have been identified as potent inducers of haem oxygenase-1 (HO-1), a redox-sensitive inducible protein that provides protection against various forms of stress. Here, we show that in renal epithelial cells both curcumin and CAPE stimulate the expression of Nrf2 in a concentration- and time-dependent manner. This effect was associated with a significant increase in HO-1 protein expression and haem oxygenase activity. From several lines of investigation we also report that curcumin (and, by inference, CAPE) stimulates ho-1 gene activity by promoting inactivation of the Nrf2-Keap1 complex, leading to increased Nrf2 binding to the resident ho-1 AREs. Moreover, using antibodies and specific inhibitors of the mitogen-activated protein kinase (MAPK) pathways, we provide data implicating p38 MAPK in curcumin-mediated ho-1 induction. Taken together, these results...