Induction of Polyamine Oxidase 1 by Helicobacter pylori Causes Macrophage Apoptosis by Hydrogen Peroxide Release and Mitochondrial Membrane Depolarization

Helicobacter pylori infects the human stomach by escaping the host immune response. One mechanism of bacterial survival and mucosal damage is induction of macrophage apoptosis, which we have reported to be dependent on polyamine synthesis by arginase and ornithine decarboxylase. During metabolic bac...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-09, Vol.279 (38), p.40161-40173
Main Authors: Chaturvedi, Rupesh, Cheng, Yulan, Asim, Mohammad, Bussière, Françoise I., Xu, Hangxiu, Gobert, Alain P., Hacker, Amy, Casero, Robert A., Wilson, Keith T.
Format: Article
Language:English
Subjects:
Acetyltransferases - genetics
Acetyltransferases - metabolism
Animal biology
Animals
Apoptosis - immunology
Caspase 3
Caspases - metabolism
Cell Line
Cytochromes c - metabolism
Enzyme Induction - physiology
Food and Nutrition
Gene Expression Regulation, Enzymologic - immunology
Helicobacter Infections - immunology
Helicobacter Infections - metabolism
Helicobacter Infections - physiopathology
Helicobacter pylori
Hydrogen Peroxide - metabolism
Immunology
In Situ Nick-End Labeling
Life Sciences
Macrophages - cytology
Macrophages - enzymology
Macrophages - microbiology
Membrane Potentials - physiology
Mice
Microbiology and Parasitology
Mitochondria - physiology
Ornithine Decarboxylase - genetics
Ornithine Decarboxylase - metabolism
Oxidoreductases Acting on CH-NH Group Donors - genetics
Oxidoreductases Acting on CH-NH Group Donors - metabolism
Parasitology
Polyamine Oxidase
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Summary:Helicobacter pylori infects the human stomach by escaping the host immune response. One mechanism of bacterial survival and mucosal damage is induction of macrophage apoptosis, which we have reported to be dependent on polyamine synthesis by arginase and ornithine decarboxylase. During metabolic back-conversion, polyamines are oxidized and release H2O2, which can cause apoptosis by mitochondrial membrane depolarization. We hypothesized that this mechanism is induced by H. pylori in macrophages. Polyamine oxidation can occur by acetylation of spermine or spermidine by spermidine/spermine N1-acetyltransferase prior to back-conversion by acetylpolyamine oxidase, but recently direct conversion of spermine to spermidine by the human polyamine oxidase h1, also called spermine oxidase, has been demonstrated. H. pylori induced expression and activity of the mouse homologue of this enzyme (polyamine oxidase 1 (PAO1)) by 6 h in parallel with ornithine decarboxylase, consistent with the onset of apoptosis, while spermidine/spermine N1-acetyltransferase activity was delayed until 18 h when late stage apoptosis had already peaked. Inhibition of PAO1 by MDL 72527 or by PAO1 small interfering RNA significantly attenuated H. pylori-induced apoptosis. Inhibition of PAO1 also significantly reduced H2O2 generation, mitochondrial membrane depolarization, cytochrome c release, and caspase-3 activation. Overexpression of PAO1 by transient transfection induced macrophage apoptosis. The importance of H2O2 was confirmed by inhibition of apoptosis with catalase. These studies demonstrate a new mechanism for pathogen-induced oxidative stress in macrophages in which activation of PAO1 leads to H2O2 release and apoptosis by a mitochondrial-dependent cell death pathway, contributing to deficiencies in host defense in diseases such as H. pylori infection.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M401370200