アカギリ　サトミ   Akagiri Satomi   赤桐　里美    所属   医学研究科 医学研究科 (医学部医学科をご参照ください)    職種   特任助教
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Lansoprazole, a proton pump inhibitor, mediates anti-inflammatory effect in gastric mucosal cells through the induction of heme oxygenase-1 via activation of NF-E2-related factor 2 and oxidation of kelch-like ECH-associating protein 1.
掲載誌名	正式名：The Journal of pharmacology and experimental therapeutics 略　 称：J Pharmacol Exp Ther ISSNコード：15210103/00223565
巻・号・頁	331(1),pp.255-264
著者・共著者	Takagi Tomohisa, Naito Yuji, Okada Hitomi, Ishii Takeshi, Mizushima Katsura, Akagiri Satomi, Adachi Satoko, Handa Osamu, Kokura Satoshi, Ichikawa Hiroshi, Itoh Ken, Yamamoto Masayuki, Matsui Hirofumi, Yoshikawa Toshikazu
発行年月	2009/10
概要	Induction of heme oxygenase-1 (HO-1) expression has been associated with cytoprotective and anti-inflammatory actions of lansoprazole, a proton pump inhibitor, but the underlying molecular mechanisms remain largely unresolved. In this study, we investigate the role of transcriptional NF-E2-related factor 2 (Nrf2), its phosphorylation/activation, and oxidation of Kelch-like ECH-associating protein 1 (Keap1) in lansoprazole-induced HO-1 up-regulation using cultured gastric epithelial cells (rat gastric mucosal cell line, RGM-1). HO-1 expression of RGM-1 cells was markedly enhanced in a time- and dose-dependent manner by the treatment with lansoprazole, and this up-regulation of HO-1 contributed to the inhibition of chemokine production from stimulated RGM-1 cells. Transfection of Nrf2-siRNA suppressed the lansoprazole-induced HO-1. An electrophoretic mobility shift assay showed increases in the nuclear translocation and stress-response elements (StRE) binding activity of Nrf2 proteins in RGM-1 cells treated with lansoprazole. Furthermore, in RGM-1 cells transfected with HO-1 enhancer luciferase reporter plasmid containing mutant StRE, lansoprazole-induced HO-1 reporter gene activity was diminished. Lansoprazole promoted the phosphorylation of extracellular signal-regulated kinase (ERK), and lansoprazole-induced HO-1 up-regulation was suppressed by U0126, an ERK-specific inhibitor. Phosphorylated Nrf2 protein was detected in the phosphoprotein fraction purified by a Pro-Q Diamond Phosphoprotein Enrichment kit. Finally, an oxidative form of the Keap1 protein was detected in lansoprazole-treated RGM-1 cells by analyzing S-oxidized proteins using biotinylated cysteine as a molecular probe. These results indicate that lansoprazole up-regulates HO-1 expression in rat gastric epithelial cells, and the up-regulated HO-1 contributes to the anti-inflammatory effects of the drug. Phosphorylation of ERK and Nrf2, activation and nuclear translocation of Nrf2, and oxidation of Keap
DOI	10.1124/jpet.109.152702
PMID	19628634