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NF-B Activation during Acute Helicobacter pylori Infection in Mice

Richard L. Ferrero,^1* Patrick Avé,² Delphine Ndiaye,³ Jean-Christophe Bambou,^1, Michel R. Huerre,² Dana J. Philpott,^4, and Sylvie Mémet^3*

Unité de Pathogénie Bactérienne des Muqueuses,¹ Unité de Recherche et d'Expertise Histotechnologie et Pathologie,² Unité de Biologie Moléculaire de l'Expression Génique,³ Groupe d'Immunité Innée et Signalisation, Institut Pasteur, 25-28 rue du Dr Roux, Paris 75724, France⁴

Received 9 August 2007/ Returned for modification 17 September 2007/ Accepted 27 November 2007

Nuclear factor B (NF-B) plays a key regulatory role in host cell responses to Helicobacter pylori infection in humans. Although mice are routinely used as a model to study H. pylori pathogenesis, the role of NF-B in murine cell responses to helicobacters has not been studied in detail. We thus investigated the abilities of different Helicobacter isolates to induce NF-B-dependent responses in murine gastric epithelial cells (GECs) and in transgenic mice harboring an NF-B-responsive lacZ reporter gene. H. pylori and Helicobacter felis strains up-regulated the synthesis in mouse GECs of the NF-B-dependent chemokines KC (CXCL1) and MIP-2 (CXCL2). These responses were cag pathogenicity island (cagPAI) independent and could be abolished by pretreatment with a pharmacological inhibitor of NF-B. Consistent with the in vitro data, experimental Helicobacter infection of transgenic mice resulted in increased numbers of GECs with nuclear β-galactosidase activity, which is indicative of specific NF-B activation. The numbers of β-galactosidase-positive cells in mice were significantly increased at day 1 postinoculation with wild-type H. pylori strains harboring or not harboring a functional cagPAI, compared to naive animals (P = 0.007 and P = 0.04, respectively). Strikingly, however, no differences were observed in the levels of gastric NF-B activation at day 1 postinoculation with H. felis or at day 30 or 135 postinoculation with H. pylori. This work demonstrates for the first time the induction of NF-B activation within gastric mucosal cells during acute H. pylori infection. Furthermore, the data suggest that helicobacters may be able to regulate NF-B signaling during chronic infection.

Published ahead of print on 10 December 2007.

Editor: B. A. McCormick

Present address: INRA Unité de Recherches Zootechniques, Guadeloupe, France.

Present address: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.