Helicobacter pylori induces macrophage apoptosis by activation of arginase II

Alain P. Gobert, Yulan Cheng, Jian Ying Wang, Jean Luc Boucher, Ramaswamy K. Iyer, Stephen D. Cederbaum, Robert A. Casero, Jamie C. Newton, Keith T. Wilson

Research output: Contribution to journalArticlepeer-review

Abstract

Helicobacter pylori infection induces innate immune responses in macrophages, contributing to mucosal inflammation and damage. Macrophage apoptosis is important in the pathogenesis of mucosal infections but has not been studied with H. pylori. NO derived from inducible NO synthase (iNOS) can activate macrophage apoptosis. Arginase competes with iNOS by converting L-arginine to L-ornithine. Since we reported that H. pylori induces iNOS in macrophages, we now determined whether this bacterium induces arginase and the effect of this activation on apoptosis. NF-κB-dependent induction of arginase II, but not arginase I, was observed in RAW 264.7 macrophages cocultured with H. pylori. The time course of apoptosis matched those of both arginase and iNOS activities. Surprisingly, apoptosis was blocked by the arginase inhibitors Nω-hydroxy-L-arginine or Nω-hydroxy-nor-L-arginine, but not by the iNOS inhibitor N-iminoethyl-L-lysine. These findings were confirmed in peritoneal macrophages from iNOS-deficient mice and were not dependent on bacterial-macrophage contact. Ornithine decarboxylase (ODC), which metabolizes L-ornithine to polyamines, was also induced in H. pylori-stimulated macrophages. Apoptosis was abolished by inhibition of ODC and was restored by the polyamines spermidine and spermine. We also demonstrate that arginase H expression is up-regulated in both murine and human H. pylori gastritis tissues, indicating the likely in vivo relevance of our findings. Therefore, we describe arginase- and ODC-dependent macrophage apoptosis, which implicates polyamines in the pathophysiology of H. pylori infection.

Original languageEnglish (US)
Pages (from-to)4692-4700
Number of pages9
JournalJournal of Immunology
Volume168
Issue number9
DOIs
StatePublished - May 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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