In:
Infection and Immunity, American Society for Microbiology, Vol. 75, No. 9 ( 2007-09), p. 4305-4315
Abstract:
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 α 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 .
Type of Medium:
Online Resource
ISSN:
0019-9567
,
1098-5522
DOI:
10.1128/IAI.00578-07
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2007
detail.hit.zdb_id:
1483247-1
