| Polyamines Impair Immunity to Helicobacter pylori by Inhibiting L-Arginine Uptake Required for Nitric Oxide Production. | |
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MedLine Citation:
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PMID: 20600019 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Rupesh Chaturvedi; Mohammad Asim; Svea Hoge; Nuruddeen D Lewis; Kshipra Singh; Daniel P Barry; Thibaut de Sablet; M Blanca Piazuelo; Aditya R Sarvaria; Yulan Cheng; Ellen I Closs; Robert A Casero; Alain P Gobert; Keith T Wilson |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-07-01 |
Journal Detail:
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Title: Gastroenterology Volume: 139 ISSN: 1528-0012 ISO Abbreviation: Gastroenterology Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-01 Completed Date: 2010-11-30 Revised Date: 2011-11-01 |
Medline Journal Info:
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Nlm Unique ID: 0374630 Medline TA: Gastroenterology Country: United States |
Other Details:
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Languages: eng Pagination: 1686-98, 1698.e1-6 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arginine / antagonists & inhibitors*, metabolism Cationic Amino Acid Transporter 2 / biosynthesis, genetics Cells, Cultured Disease Models, Animal Gastric Mucosa / metabolism*, microbiology Gastritis / metabolism, microbiology, pathology Gene Expression Regulation Helicobacter Infections / immunology*, metabolism, microbiology Helicobacter pylori / immunology, pathogenicity* Humans Immunity, Cellular / physiology* Macrophages / immunology, metabolism Mice Mice, Inbred C57BL Nitric Oxide / biosynthesis* Nitric Oxide Synthase Type II / biosynthesis, genetics Ornithine Decarboxylase / biosynthesis, genetics Polyamines / pharmacology RNA / genetics Reverse Transcriptase Polymerase Chain Reaction Spermine / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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F31 GM083500-03/GM/NIGMS NIH HHS; F31GM083500/GM/NIGMS NIH HHS; P01 CA028842-245215/CA/NCI NIH HHS; P01 CA116087-02/CA/NCI NIH HHS; P01CA028842/CA/NCI NIH HHS; P01CA116087/CA/NCI NIH HHS; P30DK058404/DK/NIDDK NIH HHS; R01 AT004821-02/AT/NCCAM NIH HHS; R01 AT004821-04/AT/NCCAM NIH HHS; R01 CA051085-14A1/CA/NCI NIH HHS; R01 CA098454-05A2/CA/NCI NIH HHS; R01 CA098454-07/CA/NCI NIH HHS; R01 CA098454-08/CA/NCI NIH HHS; R01 DK053620-10/DK/NIDDK NIH HHS; R01AT004821/AT/NCCAM NIH HHS; R01CA051085/CA/NCI NIH HHS; R01CA098454/CA/NCI NIH HHS; R01DK053620/DK/NIDDK NIH HHS; T32 CA009592-20S1/CA/NCI NIH HHS; T32 DK007673-16/DK/NIDDK NIH HHS; T32CA009592/CA/NCI NIH HHS; T32DK007673/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cationic Amino Acid Transporter 2; 0/Polyamines; 10102-43-9/Nitric Oxide; 63231-63-0/RNA; 71-44-3/Spermine; 74-79-3/Arginine; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 4.1.1.17/Ornithine Decarboxylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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