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J. Biol. Chem., Vol. 280, Issue 4, 2409-2412, January 28, 2005

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Spermine Causes Loss of Innate Immune Response to Helicobacter pylori by Inhibition of Inducible Nitric-oxide Synthase Translation^*

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

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

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.

Received for publication, October 22, 2004 , and in revised form, November 9, 2004.

^* This work was supported by the National Institutes of Health Grants DK53620 and DK63626 (to K. T. W.) and CA51085 and CA98454 (to R. A. C.) and grants from the Office of Medical Research, Department of Veterans of Affairs (to K. T. W.) and the Crohn's & 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, Inst. 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; E-mail: kwilson{at}umaryland.edu.

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