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J. Biol. Chem., Vol. 279, Issue 38, 40161-40173, September 17, 2004

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

Rupesh Chaturvedi, Yulan Cheng, Mohammad Asim, Françoise I. Bussière, Hangxiu Xu, Alain P. Gobert¶, Amy Hacker||, Robert A. Casero, Jr.||, and Keith T. Wilson**

From the Department of Medicine, Division of Gastroenterology and the ^**Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, the Veterans Affairs Maryland Health Care System, Baltimore, Maryland, 21201, and the ^||Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21231

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.

Received for publication, February 8, 2004 , and in revised form, July 7, 2004.

^* This work was supported by National Institutes of Health Grants DK53620 and DK63626 (to K. T. W.) and CA51085 and CA98454 (to R. A. C.), the Office of Medical Research, Department of Veterans of Affairs (to K. T. W.), and the Crohn's and Colitis Foundation of America (to K. T. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Present address: Unité de Microbiologie, Institut National de la Recherche Agronomique de Clermont-Ferrand-Theix, 63122 Saint-Genès-Champanelle, France.

To whom correspondence should be addressed: University of Maryland School of Medicine, 22 South Greene St., Rm. N3W62, Baltimore, MD 21201. Tel.: 410-706-1471; Fax: 410-706-1573; E-mail: kwilson{at}umaryland.edu.

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