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OtherGASTROINTESTINAL, HEPATIC, PULMONARY, and RENAL

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

Tomohisa Takagi, Yuji Naito, Hitomi Okada, Takeshi Ishii, Katsura Mizushima, Satomi Akagiri, Satoko Adachi, Osamu Handa, Satoshi Kokura, Hiroshi Ichikawa, Ken Itoh, Masayuki Yamamoto, Hirofumi Matsui and Toshikazu Yoshikawa
Journal of Pharmacology and Experimental Therapeutics October 2009, 331 (1) 255-264; DOI: https://doi.org/10.1124/jpet.109.152702
Tomohisa Takagi
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Yuji Naito
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Hitomi Okada
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Takeshi Ishii
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Katsura Mizushima
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Satomi Akagiri
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Satoko Adachi
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Osamu Handa
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Satoshi Kokura
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Hiroshi Ichikawa
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Ken Itoh
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Masayuki Yamamoto
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Hirofumi Matsui
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Toshikazu Yoshikawa
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Abstract

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 Keap1 are all involved in the lansoprazole-induced HO-1 up-regulation.

  • PPI, proton pump inhibitor
  • HO-1, heme oxygenase-1
  • HO, heme oxygenase
  • LPS, lipopolysaccharide
  • MAPK, mitogen-activated protein kinase
  • Nrf2, NF-E2-related factor 2
  • Keap1, Kelch-like ECH-associating protein 1
  • SnPP, tin-protoporphyrin
  • U0126, 1,4-diamino-2,3-dicyano-1,4-bis-(methylthio)butadiene
  • ERK, extracellular signal-regulated kinase
  • JNK, Jun N-terminal kinase
  • SP600125, anthra[1,9-cd] pyrazol-6 (2H)-one
  • IL, interleukin
  • CINC-1, cytokine-induced neutrophil chemoattractant-1
  • ELISA, enzyme-linked immunosorbent assay
  • PBS, phosphate-buffered saline
  • HRP, horseradish peroxidase
  • PCR, polymerase chain reaction
  • PAGE, polyacrylamide gel electrophoresis
  • PVDF, polyvinylidene difluoride
  • TBS-T, Tris-buffered saline and 0.1% Tween 20
  • ECL, enhanced chemiluminescence
  • siRNA, small interfering RNA
  • EMSA, electrophoretic mobility shift assay
  • StRE, stress-responsive DNA element
  • bZIP, basic-leucine zipper
  • SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole
  • GRO, growth-regulated oncogene.

Footnotes

  • This work was supported by a grant-in-aid for scientific research from the Ministry of Health, Labor and Welfare of Japan [Grant 18590694].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • ABBREVIATIONS:

    • Received March 3, 2009.
    • Accepted July 22, 2009.
  • © 2009 by the American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 382 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 2
1 Aug 2022
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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
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OtherGASTROINTESTINAL, HEPATIC, PULMONARY, and RENAL

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

Tomohisa Takagi, Yuji Naito, Hitomi Okada, Takeshi Ishii, Katsura Mizushima, Satomi Akagiri, Satoko Adachi, Osamu Handa, Satoshi Kokura, Hiroshi Ichikawa, Ken Itoh, Masayuki Yamamoto, Hirofumi Matsui and Toshikazu Yoshikawa
Journal of Pharmacology and Experimental Therapeutics October 1, 2009, 331 (1) 255-264; DOI: https://doi.org/10.1124/jpet.109.152702

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OtherGASTROINTESTINAL, HEPATIC, PULMONARY, and RENAL

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

Tomohisa Takagi, Yuji Naito, Hitomi Okada, Takeshi Ishii, Katsura Mizushima, Satomi Akagiri, Satoko Adachi, Osamu Handa, Satoshi Kokura, Hiroshi Ichikawa, Ken Itoh, Masayuki Yamamoto, Hirofumi Matsui and Toshikazu Yoshikawa
Journal of Pharmacology and Experimental Therapeutics October 1, 2009, 331 (1) 255-264; DOI: https://doi.org/10.1124/jpet.109.152702
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