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J. Biol. Chem., Vol. 281, Issue 17, 11637-11648, April 28, 2006
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Nucleotide-binding Oligomerization Domain-1 and Epidermal Growth Factor Receptor
CRITICAL REGULATORS OF 
-DEFENSINS DURING HELICOBACTER PYLORI INFECTION*
23
From the
Infectious Diseases and Microbiology Unit, Institute of Child Health, 30 Guildford St, London WC1N 1EH, United Kingdom, the Institute of Infection, Immunity, and Inflammation, and the Wolfson Digestive Diseases Centre, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom, the ¶Department of Pathology and Comprehensive Cancer Center, the University of Michigan Medical School, Ann Arbor, Michigan 48109, the **Department of Biochemistry, Trinity College, Dublin 2, Ireland, the ||Laboratory of Molecular Signaling, The Babraham Institute, Babraham Hall, Cambridge CB2 4AT, United Kingdom, the Section for Clinical and Experimental Infectious Medicine, the Department of Clinical Sciences, Lund University, Biomedical Center B14, Tornavägen 10, SE-22184 Lund, Sweden, and the Research Centre for Gastroenterology, Institute of Cell and Molecular Sciences, Barts and The London, Queen Mary School of Medicine and Dentistry, London E1 2AD, United Kingdom
Host-pathogen interactions that allow Helicobacter pylori to survive and persist in the stomach of susceptible individuals remain unclear. Human -defensins (hBDs), epithelial-derived antimicrobial peptides are critical components of host-defense at mucosal surfaces. The role of H. pylori-mediated NF-
B and epidermal growth factor receptor (EGFR) activation on -defensin expression was investigated. Transient transfection studies utilizing -defensin promoter constructs were conducted in gastric cells with contribution of individual signaling events evaluated by the addition of specific inhibitors, small interference nucleotide-binding oligomerization domain 1 (NOD1) RNA or plasmids encoding Vaccinia virus proteins that interrupt interleukin-1 and Toll-like receptor signaling. The role of individual MAPK pathways was further delineated in HEK-293 cells expressing conditional MAPK mutants. We found hBD2 expression exclusively dependent on the presence of the bacterial cag pathogenicity island, with NOD1 a critical host sensor. Impairment of murine-defensin 4 (an orthologue of hBD2) expression in NOD1-deficient mice 7-days post-infection further confirmed the role of this cytoplasmic pattern-recognition receptor in eliciting host innate immunity. In contrast to hBD2, hBD3 expression was NOD1-independent but EGFR and ERK pathway-dependent. Importantly, Toll-like receptor signaling was not implicated in H. pylori-mediated hBD2 and hBD3 gene expression. The divergent signaling events governing hBD2 and hBD3 expression suggest temporal functional variation, such that hBD2 may contribute to antimicrobial barrier function during the inflammatory phase with hBD3 playing a greater role during the repair, wound healing phase of infection.
Received for publication, September 19, 2005 , and in revised form, March 1, 2006.
* This work was supported in part by The Wellcome Trust 065883 and The Royal Society (to M. B.-E.). 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 Supported by National Institutes of Health Grant R01-DK61707.
2 Supported by a Senior Clinical Fellowship from the Medical Research Council (UK).
3 To whom correspondence should be addressed. Tel.: 44-0207-905-2215; Fax: 44-0207-813-8494; E-mail: M.Bajaj-Elliott{at}ich.ucl.ac.uk.
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