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

Abstract

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.

Gene polymorphisms in the ornithine decarboxylase–polyamine pathway modify gastric cancer risk by interaction with isoflavone concentrations

“…The presence of H. pylori induces macrophage iNOS for host immunity activation, whereas spermine inhibits expression of NOS2A (encoding iNOS). Then iNOS converts L-arginine into citrulline and NO, where the latter possess antimicrobial and proinflammatory properties [12], leading to killing of H. pylori. Spermine to spermidine back-conversion by spermine oxidase, also induced by the presence of H. pylori [13], produces aldehyde (3-aminopropanal) and H 2 O 2 [14].…”

“…H. pylori infection results in inflammation and induces innate immunity in the host, which can be eradicated by host immune responses, such as nitric oxide (NO) production in macrophages. However, H. pylori-induced immune responses can fail to eradicate the bacterium by polyamine synthesis through the sequential ornithine decarboxylase (ODC)-polyamine pathway [12]. Elevated polyamine levels through the sequential ODC-polyamine pathway are associated with gastric cancer [2].…”

Polyamines and transglutaminases: future perspectives

“…Chaturvedi et al (2012) who previously reported the importance of utilizing l-arginine as a host response to the gastric pathogen Helicobacter pylori, now show that generation of antimicrobial nitric oxide (NO) by inducible NO synthase (iNOS), which is dependent on l-arginine availability, is limited by competition with arginase II activity (Lewis et al 2011) and upregulation of ODC. Spermine blocks l-arginine uptake into macrophages (Chaturvedi et al 2010) and SMO mediates DNA damage in gastric epithelial cells. Three articles on this topic are included in this issue.…”

Spermine oxidase, a polyamine catabolic enzyme that linksHelicobacter pyloriCagA and gastric cancer risk

“…In our recent chemoprevention study in mice, inhibition of ODC with a-difluoromethylornithine (DFMO) and subsequent reduction in polyamines led to decreases in both H. pylori colonization and levels of gastritis. 45 In fact, we have reported that DFMO treatment has the potential benefits of both increasing antimicrobial nitric oxide production by gastric macrophages and inhibiting H. pylori growth directly. 45,46 We speculate that inhibition of polyamine synthesis could have an additional benefit of reducing oxidative stress and subsequently DNA damage by depleting polyamines (Fig.…”