| Arginase II restricts host defense to Helicobacter pylori by attenuating inducible nitric oxide synthase translation in macrophages. | |
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MedLine Citation:
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PMID: 20097867 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Helicobacter pylori infection of the stomach causes peptic ulcer disease and gastric cancer. Despite eliciting a vigorous immune response, the bacterium persists for the life of the host. An important antimicrobial mechanism is the production of NO derived from inducible NO synthase (iNOS). We have reported that macrophages can kill H. pylori in vitro by an NO-dependent mechanism, but supraphysiologic levels of the iNOS substrate l-arginine are required. Because H. pylori induces arginase activity in macrophages, we determined if this restricts NO generation by reducing l-arginine availability. Inhibition of arginase with S-(2-boronoethyl)-l-cysteine (BEC) significantly enhanced NO generation in H. pylori-stimulated RAW 264.7 macrophages by enhancing iNOS protein translation but not iNOS mRNA levels. This effect resulted in increased killing of H. pylori that was attenuated with an NO scavenger. In contrast, inhibition of arginase in macrophages activated by the colitis-inducing bacterium Citrobacter rodentium increased NO without affecting iNOS levels. H. pylori upregulated levels of arginase II (Arg2) mRNA and protein, which localized to mitochondria, whereas arginase I was not induced. Increased iNOS protein and NO levels were also demonstrated by small interfering RNA knockdown of Arg2 and in peritoneal macrophages from C57BL/6 Arg2(-/-) mice. In H. pylori-infected mice, treatment with BEC or deletion of Arg2 increased iNOS protein levels and NO generation in gastric macrophages, but treatment of Arg2(-/-) mice with BEC had no additional effect. These studies implicate Arg2 in the immune evasion of H. pylori by causing intracellular depletion of l-arginine and thus reduction of NO-dependent bactericidal activity. |
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Authors:
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Nuruddeen D Lewis; Mohammad Asim; Daniel P Barry; Kshipra Singh; Thibaut de Sablet; Jean-Luc Boucher; Alain P Gobert; Rupesh Chaturvedi; Keith T Wilson |
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Publication Detail:
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Type: 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: 2010-01-22 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 184 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-02-18 Completed Date: 2010-05-04 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 2572-82 Citation Subset: AIM; IM |
Affiliation:
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Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37240, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Arginase / antagonists & inhibitors, genetics, metabolism* Boronic Acids / pharmacology Cell Line Citrobacter rodentium / growth & development, physiology Flow Cytometry Helicobacter Infections / genetics, metabolism, microbiology Helicobacter pylori / growth & development*, physiology Host-Pathogen Interactions Immunoblotting Macrophages / cytology, metabolism*, microbiology Macrophages, Peritoneal / cytology, metabolism, microbiology Male Mice Mice, Inbred C57BL Mice, Knockout Mitochondria / enzymology Nitric Oxide / metabolism Nitric Oxide Synthase Type II / genetics, metabolism* Protein Biosynthesis RNA Interference Reverse Transcriptase Polymerase Chain Reaction |
| Grant Support | |
ID/Acronym/Agency:
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F31 GM083500-01/GM/NIGMS NIH HHS; F31GM083500/GM/NIGMS NIH HHS; P30 DK058404-03/DK/NIDDK NIH HHS; P30DK058404/DK/NIDDK NIH HHS; R01 AT004821-02/AT/NCCAM NIH HHS; R01 DK053620-10/DK/NIDDK NIH HHS; R01AT004821/AT/NCCAM NIH HHS; R01DK053620/DK/NIDDK NIH HHS; T32 CA009592-17/CA/NCI NIH HHS; T32CA009592/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/(2-boronoethyl)-cysteine; 0/Boronic Acids; 10102-43-9/Nitric Oxide; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 3.5.3.1/Arg2 protein, mouse; EC 3.5.3.1/Arginase |
| Comments/Corrections | |
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