title: Insight into the molecular mechanism of heme oxygenase-1 induction by docosahexaenoic acid in U937 cells.
abstract: Heme oxygenase-1 (HO-1) has anti-inflammatory effects on myeloid cells in response to various stimuli. To date, little is known about whether fatty acids can affect HO-1 induction. Here, we report the induction of HO-1 by docosahexaenoic acid (DHA) and the associated molecular mechanisms in human myelomonocytic lymphoma U937 cells. When U937 cells were treated with DHA, eicosapentaenoic acid, palmitic acid or oleic acid, DHA was the most effective inducer of HO-1. The activation of AKT and glycogen synthase kinase-3β did not significantly change after DHA treatment. However, DHA increased the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), but not of other mitogen-activated protein kinases such as p38 and JNK. The increase in HO-1 expression was significantly inhibited by U0126, an ERK1/2 inhibitor. Nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) and its binding to the HO-1 promoter significantly increased upon DHA treatment. An increase in intracellular reactive oxygen species was detected by dichlorofluorescein diacetate, but not by hydroethidium or 2-[6-(4-hydroxy)phenoxy-3H-xanthen-3-on-9-yl] benzoic acid after DHA treatment. Pretreatment with NAC dramatically inhibited the ERK1/2 activation, binding of Nrf-2 to antioxidant response elements (AREs) located in the HO-1 promoter and the induction of HO-1 by DHA. In conclusion, DHA increased HO-1 expression in U937 cells via activation of ERK1/2 and increased Nrf-2 binding to ARE in the HO-1 promoter. These findings will help develop better strategies for treating inflammatory disorders with DHA.
authors.affiliation: Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: sai@med.u-toyama.ac.jp.
authors.forename: Zheng-Guo
authors.initials: ZG
authors.lastname: Cui
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: ogawa@med.u-toyama.ac.jp.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ogawa
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: ktsune@med.u-toyama.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Department of Radiology, The Affiliated Hospital of Jiangnan University, Wuxi 21422, PR China. Electronic address: yangen1205@hotmail.com.
authors.forename: Gen
authors.initials: G
authors.lastname: Yan
authors.affiliation: Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: taolingling@med.u-toyama.ac.jp.
authors.forename: Lingling
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: shimo504@med.u-toyama.ac.jp.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimomura
authors.affiliation: Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: inadera@med.u-toyama.ac.jp.
authors.forename: Hidekuni
authors.initials: H
authors.lastname: Inadera
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002070:Butadienes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009570:Nitriles; D017382:Reactive Oxygen Species; C113580:U 0126; D004281:Docosahexaenoic Acids; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D000111:Acetylcysteine
keywords: DHA; ERK1/2; HO-1; Nrf-2