Polyamines impair immunity to helicobacter pylori by inhibiting L-Arginine uptake required for nitric oxide production

Rupesh Chaturvedi, Mohammad Asim, Svea Hoge, Nuruddeen D. Lewis, Kshipra Singh, Daniel P. Barry, Thibaut De Sablet, M. Blanca Piazuelo, Aditya R. Sarvaria, Yulan Cheng, Ellen I. Closs, Robert A. Casero, Alain P. Gobert, Keith T. Wilson

Research output: Contribution to journalArticle

Abstract

Background & Aims: Helicobacter pyloriinduced 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 pyloristimulated 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. Methods: Levels of the inducible cationic amino acid transporter (CAT)2, ODC, and iNOS were measured in macrophages and H pylori gastritis tissues. L-Arg uptake, iNOS expression, and NO levels were assessed in cells with small interfering RNA knockdown of CAT2 or ODC, and in gastric macrophages. The ODC inhibitor, α- difluoromethylornithine, was administered to H pyloriinfected mice for 4 months after inoculation. Results: H pylori induced CAT2 and uptake of L-Arg in RAW 264.7 or primary macrophages. Addition of spermine or knockdown of CAT2 inhibited L-Arg uptake, NO production, and iNOS protein levels, whereas knockdown of ODC had the opposite effect. CAT2 and ODC were increased in mouse and human H pylori gastritis tissues and localized to macrophages. Gastric macrophages from H pyloriinfected mice showed increased ODC expression, and attenuated iNOS and NO levels upon ex vivo H pylori stimulation versus cells from uninfected mice. α-Difluoromethylornithine treatment of infected mice restored L-Arg uptake, iNOS protein expression, and NO production in gastric macrophages, and significantly reduced both H pylori colonization levels and gastritis severity. Conclusions: Up-regulation of ODC in gastric macrophages impairs host defense against H pylori by suppressing iNOS-derived NO production.

Original languageEnglish (US)
Pages (from-to)1686-1698.e6
JournalGastroenterology
Volume139
Issue number5
DOIs
StatePublished - Nov 2010

Keywords

  • Gastritis
  • Macrophages
  • Spermine

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Chaturvedi, R., Asim, M., Hoge, S., Lewis, N. D., Singh, K., Barry, D. P., De Sablet, T., Piazuelo, M. B., Sarvaria, A. R., Cheng, Y., Closs, E. I., Casero, R. A., Gobert, A. P., & Wilson, K. T. (2010). Polyamines impair immunity to helicobacter pylori by inhibiting L-Arginine uptake required for nitric oxide production. Gastroenterology, 139(5), 1686-1698.e6. https://doi.org/10.1053/j.gastro.2010.06.060