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DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands

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Author: End, C. · Bikker, F.J. · Renner, M. · Bergmann, G. · Lyer, S. · Blaich, S. · Hudler, M. · Helmke, B. · Gassler, N. · Autschbach, F. · Ligtenberg, A.J.M. · Benner, A. · Holmskov, U. · Schirmacher, P. · Nieuw Amerongen, A.V. · Rosenstiel, P. · Sina, C. · Franke, A. · Hafner, M. · Kioschis, P. · Schreiber, S. · Poustka, A. · Mollenhauer, J.
Type:article
Date:2009
Source:European Journal of Immunology, 3, 39, 833-842
Identifier: 27874
doi: doi:10.1002/eji.200838689
Keywords: Health · Inflammatory bowel disease · Innate immunity · Mucosal immunity · Pattern recognition · Scavenger receptor cysteine-rich · Carrageenan · Deleted in malignant brain tumors 1 · Dextran sulfate · Glycoprotein · Heparan sulfate · Lipopolysaccharide · Lipoteichoic acid · Unclassified drug · Cell surface receptor · DMBT1 protein, human · Ligand · Phosphate · Animal experiment · Animal model · Antiinflammatory activity · Antimicrobial activity · Binding competition · Cell aggregation · Colitis · Controlled study · Crohn disease · Cytotoxicity · Dose response · Enzyme linked immunosorbent assay · Escherichia coli · Experimental mouse · Host pathogen interaction · Human · Human cell · In vitro study · Innate immunity · Intestine epithelium cell · Mouse · Nonhuman · Protein binding · Protein determination · Protein expression · Protein function · Protein motif · Protein phosphorylation · Salmonella minnesota · Salmonella typhimurium · Streptococcus gordonii · Sulfation · Bacterium · Cell line · Drug antagonism · Epithelium cell · Genetics · Immunology · Intestine · Metabolism · Microbiology · Bacteria · Carrageenan · Cell Line · Dextran Sulfate · Epithelial Cells · Humans · Intestines · Ligands · Phosphates · Receptors, Cell Surface

Abstract

Deleted in malignant brain tumors 1 (DMBT1) is a secreted glycoprotein displaying a broad bacterial-binding spectrum. Recent functional and genetic studies linked DMBT1 to the suppression of LPS-induced TLR4-mediated NF-kappaB activation and to the pathogenesis of Crohn's disease. Here, we aimed at unraveling the molecular basis of its function in mucosal protection and of its broad pathogen-binding specificity. We report that DMBT1 directly interacts with dextran sulfate sodium (DSS) and carrageenan, a structurally similar sulfated polysaccharide, which is used as a texturizer and thickener in human dietary products. However, binding of DMBT1 does not reduce the cytotoxic effects of these agents to intestinal epithelial cells in vitro. DSS and carrageenan compete for DMBT1-mediated bacterial aggregation via interaction with its bacterial-recognition motif. Competition and ELISA studies identify poly-sulfated and poly-phosphorylated structures as ligands for this recognition motif, such as heparansulfate, LPS, and lipoteichoic acid. Dose-response studies in Dmbt1(-/-) and Dmbt1(+/+) mice utilizing the DSS-induced colitis model demonstrate a differential response only to low but not to high DSS doses. We propose that DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands providing a molecular basis for its broad bacterial-binding specificity and its inhibitory effects on LPS-induced TLR4-mediated NF-kappaB activation. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.