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  • 1
    Keywords: brain ; SPECTRA ; CELLS ; IN-VITRO ; tumor ; AGENTS ; CELL ; human ; MODEL ; VITRO ; DISEASE ; TUMORS ; MICE ; ACTIVATION ; LIGAND ; BINDING ; SUPPRESSION ; MOLECULE ; RECOGNITION ; ACID ; GLYCOPROTEIN ; PATHOGENESIS ; DOSE-RESPONSE ; LIGANDS ; EPITHELIAL-CELLS ; specificity ; DMBT1 ; AGENT ; AGGREGATION ; MOTIF ; PRODUCTS ; brain tumor ; BRAIN-TUMORS ; COLITIS ; interaction ; SODIUM ; pattern recognition ; structure ; brain tumors ; LPS ; Genetic ; genetic study ; BRAIN-TUMOR ; A
    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.
    Type of Publication: Journal article published
    PubMed ID: 19189310
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  • 2
    Keywords: brain ; RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; INVASION ; tumor ; CELL ; Germany ; VITRO ; DISEASE ; GENE ; PROTEIN ; PROTEINS ; COMPONENTS ; TUMORS ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; BINDING ; RECOGNITION ; TARGET ; MUTATION ; COMPONENT ; LINE ; MUTATIONS ; EPITHELIAL-CELLS ; FACTOR-KAPPA-B ; NF-kappa B ; TNF-ALPHA ; SALIVARY AGGLUTININ ; SURFACTANT PROTEIN-D ; INFLAMMATORY-BOWEL-DISEASE ; MALIGNANT BRAIN-TUMORS ; SCAVENGER RECEPTOR ; CYTOKINE ; BRAIN-TUMORS ; STREPTOCOCCUS-MUTANS ; secretion ; PATHOGENS ; USA ; function ; immunology ; INHIBIT ; CYSTEINE-RICH DOMAINS ; DYSFUNCTION ; PURPLE SEA-URCHIN ; SEROTYPE-C STRAIN
    Abstract: 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-alpha, LPS). We demonstrate that DMBT1 is a target gene for the intracellular pathogen receptor NOD2 via NF-kappa 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-kappa 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
    Type of Publication: Journal article published
    PubMed ID: 17548659
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