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Regulation of DMBT1 via NOD2 and TLR4 in Intestinal Epithelial Cells Modulates Bacterial Recognition and Invasion¹

Philip Rosenstiel^2,*, Christian Sina^2,*, Caroline End^,, Marcus Renner, Stefan Lyer, Andreas Till^*, Stephan Hellmig, Susanna Nikolaus^*,, Ulrich R. Fölsch, Burkhard Helmke^¶, Frank Autschbach^¶, Peter Schirmacher^¶, Petra Kioschis, Mathias Hafner, Annemarie Poustka, Jan Mollenhauer^3, and Stefan Schreiber^3,4,*

^* Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Kiel, Germany; Division of Molecular Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany; Institute of Molecular Biology and Cell Culture Technology, University of Applied Sciences Mannheim, Mannheim, Germany; Department of General Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany; and ^¶ Institute of Pathology, University of Heidelberg, Heidelberg, Germany

Mucosal epithelial cell layers are constantly exposed to a complex resident microflora. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by pathogen binding. This report describes the regulation and function of DMBT1 in intestinal epithelial cells, which form the primary immunological barrier for invading pathogens. We report that intestinal epithelial cells up-regulate DMBT1 upon proinflammatory stimuli (e.g., TNF-, LPS). We demonstrate that DMBT1 is a target gene for the intracellular pathogen receptor NOD2 via NF-B activation. DMBT1 is strongly up-regulated in the inflamed intestinal mucosa of Crohn’s disease patients with wild-type, but not with mutant NOD2. We show that DMBT1 inhibits cytoinvasion of Salmonella enterica and LPS- and muramyl dipeptide-induced NF-B activation and cytokine secretion in vitro. Thus, DMBT1 may play an important role in the first line of mucosal defense conferring immune exclusion of bacterial cell wall components. Dysregulated intestinal DMBT1 expression due to mutations in the NOD2/CARD15 gene may be part of the complex pathophysiology of barrier dysfunction in Crohn’s disease.

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 the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (NGFN2-Pathway Mapping) and Deutsche Forschungsgemeinschaft (SFB617), and by Deutsche Krebshilfe Grant 1835-Mo I, Wilhelm Sander-Stiftung Grant 99.018.2, Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie/AIF Grant aFuE-1708701, MWKBW Grant ZAV-Biotech23-7532.450-3/12, and the Future Award of the HGF Impulse and Networking Funds.

² P.R. and C.S. contributed equally to this work.

³ J.M. and S.S. share senior authorship.

⁴ Address correspondence and reprint requests to Dr. Stefan Schreiber, Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrache 12, Kiel, Germany. E-mail address: s.schreiber{at}mucosa.de

⁵ Abbreviations used in this paper: DMBT1, deleted in malignant brain tumors 1; rhDMBT1, recombinant human DMBT1; SRCR, scavenger receptor cysteine-rich; CD, Crohn’s disease; MDP, muramyl dipeptide; NOD2, nucleotide binding and oligomerization domain 2; PAMP, pathogen-associated molecular pattern; IEC, intestinal epithelial cell; pIEC, primary IEC; SNP, single-nucleotide polymorphism; SAG, salivary agglutinin; IBD, inflammatory bowel disease; LB, Luria-Bertani; siRNA, small interfering RNA; wt, wild type.

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