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

Bussière FI, Chaturvedi R, Cheng Y, Gobert AP, Asim M, Blumberg DR, Xu H, Kim PY, Hacker A, Casero RA, Wilson KT
J Biol Chem. 2005 280 (4): 2409-12

PMID: 15548540 · DOI:10.1074/jbc.C400498200

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 up-regulation 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.

MeSH Terms (25)

Animals Apoptosis Cell Line Coculture Techniques Dose-Response Relationship, Drug Helicobacter pylori Immune System Immunoblotting Immunoprecipitation Macrophages Male Mice Mice, Inbred C57BL Monocytes Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type II Protein Biosynthesis Reverse Transcriptase Polymerase Chain Reaction Risk RNA, Small Interfering Spermine Stomach Neoplasms Transfection Up-Regulation

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