Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element.
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 demonstrate that induction of HO-1 by curcumin and CAPE requires the activation of the Nrf2/ARE pathway.
Balogun
Elisabeth
E
Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, UK.
Hoque
Martha
M
Gong
Pengfei
P
Killeen
Erin
E
Green
Colin J
CJ
Foresti
Roberta
R
Alam
Jawed
J
Motterlini
Roberto
R
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D002109:Caffeic Acids / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology; D003474:Curcumin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D018374:LLC-PK1 Cells; D051267:NF-E2-Related Factor 2; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*
D000975:Antioxidants; D002109:Caffeic Acids; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; D015534:Trans-Activators; D006419:Heme Oxygenase (Decyclizing); C055494:caffeic acid phenethyl ester; D003474:Curcumin; D010626:Phenylethyl Alcohol