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Infection and Immunity, September 2007, p. 4305-4315, Vol. 75, No. 9
0019-9567/07/$08.00+0     doi:10.1128/IAI.00578-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

L-Arginine Availability Regulates Inducible Nitric Oxide Synthase-Dependent Host Defense against Helicobacter pylori{triangledown}

Rupesh Chaturvedi,1,2 Mohammad Asim,1,2 Nuruddeen D. Lewis,2,3 Holly M. Scott Algood,1,2 Timothy L. Cover,1,2,4 Preston Y. Kim,5 and Keith T. Wilson1,2,3*

Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37212,1 Department of Medicine,2 Department of Cancer Biology,3 Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,4 Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 212015

Received 20 April 2007/ Accepted 5 June 2007

Helicobacter pylori infection of the stomach causes an active immune response that includes stimulation of inducible nitric oxide (NO) synthase (iNOS) expression. Although NO can kill H. pylori, the bacterium persists indefinitely, suggesting that NO production is inadequate. We determined if the NO derived from iNOS in macrophages was dependent on the availability of its substrate, L-arginine (L-Arg). Production of NO by H. pylori-stimulated RAW 264.7 cells was dependent on the L-Arg concentration in the culture medium, and the 50% effective dose for L-Arg was 220 µM, which is above reported plasma L-Arg levels. While iNOS mRNA induction was L-Arg independent, iNOS protein increased in an L-Arg-dependent manner that did not involve changes in iNOS protein degradation. L-Lysine, an inhibitor of L-Arg uptake, attenuated H. pylori-stimulated iNOS protein expression, translation, NO levels, and killing of H. pylori. While L-Arg starvation suppressed global protein translation, at concentrations of L-Arg at which iNOS protein was only minimally expressed in response to H. pylori, global translation was fully restored and eukaryotic translation initiation factor {alpha} was dephosphorylated. H. pylori lacking the gene rocF, which codes for a bacterial arginase, induced higher levels of NO production by increasing iNOS protein levels. When murine gastric macrophages were activated with H. pylori, supraphysiologic levels of L-Arg were required to permit iNOS protein expression and NO production. These findings indicate that L-Arg is rate limiting for iNOS translation and suggest that the levels of L-Arg that occur in vivo do not permit sufficient NO generation by the host to kill H. pylori.

* Corresponding author. Mailing address: Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, 1030C MRB IV, 2215B Garland Ave., Nashville, TN 37232. Phone: (615) 343-5675. Fax: (615) 343-6229. E-mail: keith.wilson{at}vanderbilt.edu

{triangledown} Published ahead of print on 11 June 2007.

Editor: A. D. O'Brien

Infection and Immunity, September 2007, p. 4305-4315, Vol. 75, No. 9
0019-9567/07/$08.00+0     doi:10.1128/IAI.00578-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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