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

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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.

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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 N 1-acetyltransferase

APAO:

Acetyl polyamine oxidase

EGFR:

Epidermal growth factor

WT:

Wild type

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Acknowledgments

This work was supported by the National Institutes of Health grants R01DK053620, R01AT004821, 3R01AT004821-02S1, P01CA028842, and P01CA116087 (to K.T.W.), the Flow Cytometry Core of the Vanderbilt University Digestive Disease Research Center grant (P30DK058404), a Merit Review Grant from the Office of Medical Research, Department of Veterans Affairs (to K.T.W.), and the Philippe Foundation (T.S. and A.P.G.).

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, 1030C MRBIV, 2215 Garland Avenue, Nashville, TN, 37232, USA

    Rupesh Chaturvedi, Thibaut de Sablet, Lori A. Coburn, Alain P. Gobert & Keith T. Wilson

  2. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Keith T. Wilson

  3. Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA

    Rupesh Chaturvedi, Thibaut de Sablet, Lori A. Coburn, Alain P. Gobert & Keith T. Wilson

  4. Institut National de la Recherche Agronomique, Unité de Microbiologie UR454, Saint-Genès-Champanelle, France

    Alain P. Gobert

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  1. Rupesh Chaturvedi
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Correspondence to Keith T. Wilson.

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Chaturvedi, R., de Sablet, T., Coburn, L.A. et al. Arginine and polyamines in Helicobacter pylori-induced immune dysregulation and gastric carcinogenesis. Amino Acids 42, 627–640 (2012). https://doi.org/10.1007/s00726-011-1038-4

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