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J. Biol. Chem., Vol. 281, Issue 4, 2005-2011, January 27, 2006

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NOD2/CARD15 Mediates Induction of the Antimicrobial Peptide Human Beta-defensin-2^*

Eske Voss, Jan Wehkamp, Kai Wehkamp, Eduard F. Stange¶, Jens M. Schröder, and Jürgen Harder1

From the Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany, the Department of Medical Microbiology and Immunology, University of California School of Medicine, Davis, California 95616, and the ^¶Department of Internal Medicine I, Robert Bosch Hospital, 70376 Stuttgart, Germany

Production of inducible antimicrobial peptides offers a first and rapid defense response of epithelial cells against invading microbes. Human beta-defensin-2 (hBD-2) is an antimicrobial peptide induced in various epithelia upon extracellular as well as intracellular bacterial challenge. Nucleotide-binding oligomerization domain protein 2 (NOD2/CARD15) is a cytosolic protein involved in intracellular recognition of microbes by sensing peptidoglycan fragments (e.g. muramyl dipeptide). We used luciferase as a reporter gene for a 2.3-kb hBD-2 promoter to test the hypothesis that NOD2 mediates the induction of hBD-2. Activation of NOD2 in NOD2-overexpressing human embryonic kidney 293 cells through its ligand muramyl dipeptide (MDP) induced hBD-2 expression. In contrast, overexpression of NOD2 containing the 3020insC frame-shift mutation, the most frequent NOD2 variant associated with Crohn disease, resulted in defective induction of hBD-2 through MDP. Luciferase gene reporter analyses and site-directed mutagenesis experiments demonstrated that functional binding sites for NF-B and AP-1 in the hBD-2 promoter are required for NOD2-mediated induction of hBD-2 through MDP. Moreover, the NF-B inhibitor Helenalin as well as a super-repressor form of the NF-B inhibitor IB strongly inhibited NOD2-mediated hBD-2 promoter activation. Expression of NOD2 was detected in primary keratinocytes, and stimulation of these cells with MDP induced hBD-2 peptide release. In contrast, small interference RNA-mediated down-regulation of NOD2 expression in primary keratinocytes resulted in a defective induction of hBD-2 upon MDP treatment. Together, these data suggest that NOD2 serves as an intracellular pattern recognition receptor to enhance host defense by inducing the production of antimicrobial peptides such as hBD-2.

Received for publication, October 11, 2005 , and in revised form, November 22, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft (SFB 617) and the Robert Bosch Foundation, Stuttgart, Germany. 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 To whom correspondence should be addressed: Dept. of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 7, 24105 Kiel, Germany. Tel.: 49-431-5971598; Fax: 49-431-5975243; E-mail: jharder{at}dermatology.uni-kiel.de.

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