Spermine oxidase is a regulator of macrophage host response to Helicobacter pylori: Enhancement of antimicrobial nitric oxide generation by depletion of spermine

Rupesh Chaturvedi, Mohammad Asim, Daniel P. Barry, Jeanetta W. Frye, Robert A. Casero, Keith T. Wilson

Research output: Contribution to journalArticlepeer-review

Abstract

The gastric pathogen Helicobacter pylori causes peptic ulcer disease and gastric cancer. We have reported that in H. pylori-activated macrophages, nitric oxide (NO) derived from inducible NO synthase (iNOS) can kill the bacterium, iNOS protein expression is dependent on uptake of its substrate l-arginine (l-Arg), the polyamine spermine can inhibit iNOS translation by inhibiting l-Arg uptake, and inhibition of polyamine synthesis enhances NO-mediated bacterial killing. Because spermine oxidase (SMO), which back-converts spermine to spermidine, is induced in macrophages by H. pylori, we determined its role in iNOS-dependent host defense. SMO shRNA knockdown in RAW 264.7 murine macrophages resulted in a marked decrease in H. pylori-stimulated iNOS protein, but not mRNA expression, and a 90 % reduction in NO levels; NO production was also inhibited in primary murine peritoneal macrophages with SMO knockdown. There was an increase in spermine levels after H. pylori stimulation that rapidly decreased, while SMO knockdown caused a greater increase in spermine that was sustained. With SMO knockdown, l-Arg uptake and killing of H. pylori by macrophages was prevented. The overexpression of SMO by transfection of an expression plasmid prevented the H. pylori-stimulated increase in spermine levels, and led to increased l-Arg uptake, iNOS protein expression and NO production, and H. pylori killing. In two human monocytic cell lines, U937 and THP-1, overexpression of SMO caused a significant enhancement of NO production with H. pylori stimulation. By depleting spermine, SMO can abrogate the inhibitory effect of polyamines on innate immune responses to H. pylori by enhancing antimicrobial NO production.

Original languageEnglish (US)
Pages (from-to)531-542
Number of pages12
JournalAmino Acids
Volume46
Issue number3
DOIs
StatePublished - Mar 2014

Keywords

  • Gastric cancer
  • Host defense
  • Innate immune response
  • Macrophages
  • Polyamines
  • Spermine oxidase

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry

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