Polyamines Impair Immunity to Helicobacter pylori by Inhibiting L-Arginine Uptake Required for Nitric Oxide Production.

Chaturvedi R, Asim M, Hoge S, Lewis ND, Singh K, Barry DP, de Sablet T, Piazuelo MB, Sarvaria AR, Cheng Y, Closs EI, Casero RA, Gobert AP, Wilson KT
Gastroenterology. 2010 139 (5): 1686-98, 1698.e1-6

PMID: 20600019 · PMCID: PMC2967614 · DOI:10.1053/j.gastro.2010.06.060

BACKGROUND & AIMS - Helicobacter pylori-induced immune responses fail to eradicate the bacterium. Nitric oxide (NO) can kill H pylori. However, translation of inducible NO synthase (iNOS) and NO generation by H pylori-stimulated macrophages is inhibited by the polyamine spermine derived from ornithine decarboxylase (ODC), and is dependent on availability of the iNOS substrate L-arginine (L-Arg). We determined if spermine inhibits iNOS-mediated immunity by reducing L-Arg uptake into macrophages.

METHODS - Levels of the inducible cationic amino acid transporter (CAT)2, ODC, and iNOS were measured in macrophages and H pylori gastritis tissues. L-Arg uptake, iNOS expression, and NO levels were assessed in cells with small interfering RNA knockdown of CAT2 or ODC, and in gastric macrophages. The ODC inhibitor, α-difluoromethylornithine, was administered to H pylori-infected mice for 4 months after inoculation.

RESULTS - H pylori induced CAT2 and uptake of L-Arg in RAW 264.7 or primary macrophages. Addition of spermine or knockdown of CAT2 inhibited L-Arg uptake, NO production, and iNOS protein levels, whereas knockdown of ODC had the opposite effect. CAT2 and ODC were increased in mouse and human H pylori gastritis tissues and localized to macrophages. Gastric macrophages from H pylori-infected mice showed increased ODC expression, and attenuated iNOS and NO levels upon ex vivo H pylori stimulation versus cells from uninfected mice. α-Difluoromethylornithine treatment of infected mice restored L-Arg uptake, iNOS protein expression, and NO production in gastric macrophages, and significantly reduced both H pylori colonization levels and gastritis severity.

CONCLUSIONS - Up-regulation of ODC in gastric macrophages impairs host defense against H pylori by suppressing iNOS-derived NO production.

Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

MeSH Terms (22)

Animals Arginine Cationic Amino Acid Transporter 2 Cells, Cultured Disease Models, Animal Gastric Mucosa Gastritis Gene Expression Regulation Helicobacter Infections Helicobacter pylori Humans Immunity, Cellular Macrophages Mice Mice, Inbred C57BL Nitric Oxide Nitric Oxide Synthase Type II Ornithine Decarboxylase Polyamines Reverse Transcriptase Polymerase Chain Reaction RNA Spermine

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