Spermine causes loss of innate immune response to Helicobacter pylori by inhibition of inducible nitric-oxide synthase translation

Françoise I. Bussière, Rupesh Chaturvedi, Yulan Cheng, Alain P. Gobert, Mohammad Asim, Darren R. Blumberg, Hangxiu Xu, Preston Y. Kim, Amy Hacker, Robert A. Casero, Keith T. Wilson

Research output: Contribution to journalArticle

Abstract

Helicobacter pylori infection of the stomach elicits a vigorous but ineffective host immune and inflammatory response, resulting in persistence of the bacterium for the life of the host. We have reported that in macrophages, H. pylori up-regulates inducible NO synthase (iNOS) and antimicrobial NO production, but in parallel there is induction of arginase II, generating ornithine, and of ornithine decarboxylase (ODC), generating polyamines. Spermine, in particular, has been shown to restrain immune response in activated macrophages by inhibiting proinflammatory gene expression. We hypothesized that spermine could prevent the antimicrobial effects of NO by inhibiting iNOS in macrophages activated by H. pylori. Spermine did not affect the upregulation of iNOS mRNA levels but in a concentration-dependent manner significantly attenuated iNOS protein levels and NO production. Reduction in iNOS protein was due to inhibition of iNOS translation and not due to iNOS degradation. ODC knockdown with small interfering (si) RNA resulted in increased H. pylori-stimulated iNOS protein expression and NO production without altering iNOS mRNA levels. When macrophages were cocultured with H. pylori, killing of bacteria was enhanced by transfection of ODC siRNA and prevented by addition of spermine. These results identify a mechanism of immune dysregulation induced by H. pylori in which stimulated spermine synthesis by the arginase-ODC pathway inhibits iNOS translation and NO production, leading to persistence of the bacterium and risk for peptic ulcer disease and gastric cancer.

Original languageEnglish (US)
Pages (from-to)2409-2412
Number of pages4
JournalJournal of Biological Chemistry
Volume280
Issue number4
DOIs
StatePublished - Jan 28 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Bussière, F. I., Chaturvedi, R., Cheng, Y., Gobert, A. P., Asim, M., Blumberg, D. R., Xu, H., Kim, P. Y., Hacker, A., Casero, R. A., & Wilson, K. T. (2005). Spermine causes loss of innate immune response to Helicobacter pylori by inhibition of inducible nitric-oxide synthase translation. Journal of Biological Chemistry, 280(4), 2409-2412. https://doi.org/10.1074/jbc.C400498200