Amino Acids

, Volume 42, Issue 2, pp 627–640

Arginine and polyamines in Helicobacter pylori-induced immune dysregulation and gastric carcinogenesis

  • Rupesh Chaturvedi
  • Thibaut de Sablet
  • Lori A. Coburn
  • Alain P. Gobert
  • Keith T. Wilson
Minireview Article

DOI: 10.1007/s00726-011-1038-4

Cite this article as:
Chaturvedi, R., de Sablet, T., Coburn, L.A. et al. Amino Acids (2012) 42: 627. doi:10.1007/s00726-011-1038-4

Abstract

l-arginine (l-Arg) is metabolized by nitric oxide synthase and arginase enzymes. The gastric pathogen Helicobacter pylori causes peptic ulcer disease and gastric cancer. We have shown that alterations in l-Arg availability and metabolism into polyamines contribute significantly to the dysregulation of the host immune response to this infection. Nitric oxide (NO) derived from inducible NO synthase (iNOS) can kill H. pylori. There are multiple mechanisms leading to failure of this process, including competition for l-Arg substrate by H. pylori arginase, and induction of host macrophage arginase II (Arg2) and ornithine decarboxylase (ODC). Generation of spermine by ODC inhibits iNOS translation and NO-mediated H. pylori killing. Expression of ODC is dependent on formation of a unique AP-1 complex, leading to upregulation of c-Myc as a transcriptional enhancer. Macrophage apoptosis is mediated by oxidation of spermine via the enzyme spermine oxidase (SMO) that generates hydrogen peroxide (H2O2), and thus oxidative stress-induced mitochondrial membrane polarization. Our studies have demonstrated that apoptosis occurs through a pERK → pc-Fos/c-Jun → c-Myc → ODC → SMO pathway. In gastric epithelial cells, activation of oxidative stress by H. pylori is dependent on SMO induction and results in both apoptosis and DNA damage, such that inhibition or knockdown of SMO markedly attenuates these events. In summary, l-Arg metabolism by the arginase–ODC pathway and the activation of SMO leads to H. pylori-induced DNA damage and immune dysregulation through polyamine-mediated oxidative stress and impairment of antimicrobial NO synthesis. Our studies indicate novel targets for therapeutic intervention in H. pylori-associated diseases, including gastritis, ulcer disease, and gastric cancer.

Keywords

H. pylori Polyamines iNOS Gastritis 

Abbreviations

H. pylori

Helicobacter pylori

NO

Nitric oxide

iNOS

Inducible NO synthase

l-Arg

l-Arginine

Arg1

Arginase I

Arg2

Arginase II

ODC

Ornithine decarboxylase

PAO1

Polyamine oxidase 1

SMO

Spermine oxidase

H2O2

Hydrogen peroxide

ROS

Reactive oxygen species

BEC

S-(2-Boronoethyl)-l-cysteine

siRNA

Small interfering RNA

DFMO

α-Difluoromethylornithine

CAT

Cationic amino acid transporter

SSAT

Spermidine/spermine N1-acetyltransferase

APAO

Acetyl polyamine oxidase

EGFR

Epidermal growth factor

WT

Wild type

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Rupesh Chaturvedi
    • 1
    • 3
  • Thibaut de Sablet
    • 1
    • 3
  • Lori A. Coburn
    • 1
    • 3
  • Alain P. Gobert
    • 1
    • 3
    • 4
  • Keith T. Wilson
    • 1
    • 2
    • 3
  1. 1.Division of Gastroenterology, Department of MedicineVanderbilt University School of MedicineNashvilleUSA
  2. 2.Department of Cancer BiologyVanderbilt University School of MedicineNashvilleUSA
  3. 3.Veterans Affairs Tennessee Valley Healthcare SystemNashvilleUSA
  4. 4.Institut National de la Recherche AgronomiqueSaint-Genès-ChampanelleFrance

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