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Interleukin-8 Induction by Helicobacter pylori in Gastric Epithelial Cells is Dependent on Apurinic/Apyrimidinic Endonuclease-1/Redox Factor-1¹

Ann M. O’Hara^*, Asima Bhattacharyya^*, Randy C. Mifflin, Michael F. Smith^*, Kieran A. Ryan^*, Kevin G.-E. Scott^*, Makoto Naganuma^*, Antonella Casola, Tadahide Izumi, Sankar Mitra, Peter B. Ernst^* and Sheila E. Crowe^2,*

^* Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 22908; and Department of Internal Medicine, Department of Pediatrics, and Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555

Helicobacter pylori infection causes inflammation and increases the expression of IL-8 in human gastric epithelial cells. H. pylori activates NF-B and AP-1, essential transcriptional factors in H. pylori-induced IL-8 gene transcription. Although colonization creates a local oxidative stress, the molecular basis for the transition from infection to the expression of redox-sensitive cytokine genes is unknown. We recently reported that the expression of apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE-1/Ref-1), which repairs oxidative DNA damage and reductively activates transcription factors including AP-1 and NF-B, is increased in human gastric epithelia during H. pylori infection. In this study, we examine whether APE-1/Ref-1 functions in the modulation of IL-8 gene expression in H. pylori-infected human gastric epithelial cells. Small interfering RNA-mediated silencing of APE-1/Ref-1 inhibited basal and H. pylori-induced AP-1 and NF-B DNA-binding activity without affecting the nuclear translocation of these transcription factors and also reduced H. pylori-induced IL-8 mRNA and protein. In contrast, overexpression of APE-1/Ref-1 enhanced basal and H. pylori-induced IL-8 gene transcription, and the relative involvement of AP-1 in inducible IL-8 promoter activity was greater in APE-1/Ref-1 overexpressing cells than in cells with basal levels of APE-1/Ref-1. APE-1/Ref-1 inhibition also reduced other H. pylori-induced chemokine expression. By implicating APE-1/Ref-1 as an important regulator of gastric epithelial responses to H. pylori infection, these data elucidate a novel mechanism controlling transcription and gene expression in bacterial pathogenesis.

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.

¹ This work was supported by National Institutes of Health Grants RO1 DK61769-01 (to S.E.C.), RO1 ES 08457 (to S.M.), RO1 DK51677 (to P.B.E.), and R21 AI48173 (to P.B.E.). Support from the Immunology and Cell Isolation Core of the University of Virginia Digestive Health Center (National Institutes of Health Grant DK67629) is gratefully acknowledged. K.G.-E.S. was supported by the Canadian Association of Gastroenterology.

² Address correspondence and reprint requests to Dr. Sheila E. Crowe, Department of Internal Medicine, University of Virginia, Post Office Box 800708, Charlottesville, VA 22908-0708. E-mail address: scrowe{at}virginia.edu

³ Abbreviations used in this paper: PAI, pathogenicity island; APE-1/Ref-1, apurinic/apyrimidinic endonuclease-1/redox factor-1; ROS, reactive oxygen species; CT, critical threshold; HPRT, hypoxanthine phosphoribosyltransferase; siRNA, small interfering RNA.

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