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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.