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J. Biol. Chem., Vol. 280, Issue 23, 22492-22496, June 10, 2005

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Helicobacter pylori-induced Macrophage Apoptosis Requires Activation of Ornithine Decarboxylase by c-Myc^*

Yulan Cheng, Rupesh Chaturvedi, Mohammad Asim, Françoise I. Bussière, Hangxiu Xu, 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, and 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 causes chronic inflammation of the gastric mucosa that results from an ineffective immune response. We have demonstrated that one underlying mechanism is induction of macrophage apoptosis mediated by polyamines. The transcription factor c-Myc has been linked to induction of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis. We determined whether H. pylori stimulates transcriptional activation of ODC in macrophages, whether this occurs via c-Myc, and whether these events regulate activation of apoptosis. H. pylori induced a significant increase in ODC promoter activity that peaked at 6 h after stimulation and was closely paralleled by similar increases in ODC mRNA, protein, and enzyme activity. By 2 h after stimulation, c-Myc mRNA and protein expression was induced, protein was translocated to the nucleus, and there was specific binding of a consensus probe for c-Myc to nuclear extracts. Both an antennapedia-linked inhibitor of c-Myc binding (Int-H1-S6A,F8A) and transfection of a c-Myc dominant-negative construct significantly attenuated H. pylori-induced ODC promoter activity, mRNA, enzyme activity, and apoptosis in parallel. Transfection of ODC small interfering RNA inhibited ODC activity and apoptosis to the same degree as inhibition of c-Myc binding. These studies indicate that c-Myc is an important mediator of macrophage activation and may contribute to the mucosal inflammatory response to pathogens such as H. pylori by its effect on ODC.

Received for publication, March 21, 2005 , and in revised form, April 13, 2005.

^* 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.), by the Office of Medical Research, Department of Veterans of Affairs (to K. T. W.), and by 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.

^** 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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