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Infection and Immunity, October 2004, p. 5750-5758, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5750-5758.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

NF-{kappa}B- and AP-1-Mediated Induction of Human Beta Defensin-2 in Intestinal Epithelial Cells by Escherichia coli Nissle 1917: a Novel Effect of a Probiotic Bacterium

Jan Wehkamp,1*,{dagger} Jürgen Harder,2,{dagger} Kai Wehkamp,2 Birte Wehkamp-von Meissner,1 Miriam Schlee,1 Corinne Enders,3 Ulrich Sonnenborn,3 Sabine Nuding,1 Stig Bengmark,4 Klaus Fellermann,1 Jens Michael Schröder,2 and Eduard F. Stange1

Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart,1 Department of Dermatology, University Hospital Kiel, Kiel,2 Department of Biological Research, Ardeypharm GmbH, Herdecke, Germany,3 Departments of Hepatology and Surgery, University College, University of London, London, United Kingdom4

Received 2 April 2004/ Returned for modification 14 June 2004/ Accepted 20 July 2004

Little is known about the defensive mechanisms induced in epithelial cells by pathogenic versus probiotic bacteria. The aim of our study was to compare probiotic bacterial strains such as Escherichia coli Nissle 1917 with nonprobiotic, pathogenic and nonpathogenic bacteria with respect to innate defense mechanisms in the intestinal mucosal cell. Here we report that E. coli strain Nissle 1917 and a variety of other probiotic bacteria, including lactobacilli—in contrast to more than 40 different E. coli strains tested—strongly induce the expression of the antimicrobial peptide human beta-defensin-2 (hBD-2) in Caco-2 intestinal epithelial cells in a time- and dose-dependent manner. Induction of hBD-2 through E. coli Nissle 1917 was further confirmed by activation of the hBD-2 promoter and detection of the hBD-2 peptide in the culture supernatants of E. coli Nissle 1917-treated Caco-2 cells. Luciferase gene reporter analyses and site-directed mutagenesis experiments demonstrated that functional binding sites for NF-{kappa}B and AP-1 in the hBD-2 promoter are required for induction of hBD-2 through E. coli Nissle 1917. Treatment with the NF-{kappa}B inhibitor Helenalin, as well as with SP600125, a selective inhibitor of c-Jun N-terminal kinase, blocked hBD-2 induction by E. coli Nissle 1917 in Caco-2 cells. SB 202190, a specific p38 mitogen-activated protein kinase inhibitor, and PD 98059, a selective inhibitor of extracellular signal-regulated kinase 1/2, were ineffective. This report demonstrates that probiotic bacteria may stimulate the intestinal innate defense through the upregulation of inducible antimicrobial peptides such as hBD-2. The induction of hBD-2 may contribute to an enhanced mucosal barrier to the luminal bacteria.

* Corresponding author. Present address: Department of Microbiology and Immunology, One Shield Ave., Tupper Hall 3146, University of California, Davis, Davis, CA 95616. Phone: (530) 754-6679. Fax: (530) 752-8692. E-mail: jwehkamp{at}ucdavis.edu.

Editor: A. D. O'Brien

{dagger} J.W. and J.H. contributed equally to this work.

Infection and Immunity, October 2004, p. 5750-5758, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5750-5758.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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