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  • EPITHELIAL-CELLS  (6)
Keywords
  • 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: CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; GENE-EXPRESSION ; PROTEIN ; transcription ; METABOLISM ; EPITHELIA ; MONOCLONAL-ANTIBODY ; TISSUE ; TUMORS ; TISSUES ; SEQUENCE ; ACID ; ACIDS ; antibodies ; antibody ; ADENOMAS ; SURFACE ; MONOCLONAL-ANTIBODIES ; EPITHELIAL-CELLS ; fatty acids ; FATTY-ACIDS ; adenocarcinoma ; ADENOCARCINOMAS ; carcinoma,epithelial tumors,fatty acid metabolism,small intestine ; CHAIN ACYL-COA ; DEPENDENT REGULATION ; fatty acid metabolism ; SMALL-INTESTINE
    Abstract: Fatty acids are implicated in tumorigenesis, but data are limited concerning endogenous fatty acid metabolism of tumor cells in adenomas and adenocarcinomas of the small intestine. The recently cloned human acyl-CoA-synthetase 5 (ACS5) is predominantly found in the small intestine and represents a key enzyme in providing cytosolic acyl-CoA thioesters. Protein synthesis and mRNA expression of ACS5 were studied in human intestinal tissues using different methods, including a newly established monoclonal antibody. In the healthy small intestine, expression of ACS5 was restricted to the villus surface epithelium but was not detectable in enterocytes lining crypts. ACS5 protein and mRNA were progressively diminished in epithelial cells of adenomas and adenocarcinomas of the small intestine. In conclusion, altered expression of ACS5 is probably related to the adenoma-carcinoma sequence of small intestinal epithelial tumors due to an impaired acyl-CoA thioester synthesis. (C) 2003 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 14608540
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  • 3
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; human ; DIAGNOSIS ; screening ; DISEASE ; PROTEIN ; DIFFERENTIATION ; MONOCLONAL-ANTIBODY ; TISSUE ; MECHANISM ; TISSUES ; mechanisms ; antibodies ; antibody ; IDENTIFICATION ; DECREASE ; PATHOGENESIS ; MONOCLONAL-ANTIBODIES ; EPITHELIAL-CELLS ; PHENOTYPE ; PROTEIN LEVELS ; CROHNS-DISEASE ; MUCOSA ; INFLAMMATORY-BOWEL-DISEASE ; COLITIS ; ACS5,fatty acid metabolism,human,small intestine ; FATTY-ACID PATTERN ; GASTRIC METAPLASIA ; PYLORIC METAPLASIA ; TRIACSIN-C
    Abstract: Several disorders of the small intestine are associated with disturbances in villus architecture. Thus, an understanding of the molecular mechanisms associated with the differentiation of villi represents an important step in the improvement of the understanding of small intestinal pathology. Screening of antibodies from a hybridoma library led to the identification of an acyl-CoA synthetase 5-specific monoclonal antibody. Protein synthesis, mRNA expression, and the enzyme activity of acyl-CoA synthetase 5 were studied by several methods in human small intestinal tissues with Crohn's disease or coeliac disease, respectively. Acyl-CoA synthetase 5 mRNA and protein levels were substantially reduced in injured small intestinal mucosa. Moreover, impaired synthesis of the acyl-CoA synthetase 5 protein was reflected by a decrease in intramucosal enzyme activity. Subtle changes of the acyl-CoA synthetase 5 pattern correlate with conversion of intestinal epithelial cells to a gastric phenotype. These results suggest that deranged acyl-CoA synthetase 5 expression, synthesis, and activity are closely related to the state of villus architecture and epithelial homeostasis in human small intestine. Copyright (C) 2004 John Wiley Sons, Ltd
    Type of Publication: Journal article published
    PubMed ID: 14743501
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  • 4
    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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  • 5
    Keywords: brain ; RECEPTOR ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; IN-VIVO ; VIVO ; DISEASE ; RISK ; GENOME ; HYBRIDIZATION ; PROTEIN ; SAMPLE ; TISSUE ; TUMORS ; MICE ; PATIENT ; DOMAIN ; GENETIC POLYMORPHISMS ; TISSUES ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; DELETION ; IN-SITU ; prevention ; immunohistochemistry ; UP-REGULATION ; NUMBER ; PATHOGENESIS ; DISPLAY ; HUMAN GENOME ; SURFACE ; EPITHELIAL-CELLS ; genetic polymorphism ; NORMAL TISSUE ; CHAIN-REACTION ; SMALL-INTESTINE ; ULCERATIVE-COLITIS ; TERMINAL DIFFERENTIATION ; inflammation ; SALIVARY AGGLUTININ ; SURFACTANT PROTEIN-D ; INFLAMMATORY-BOWEL-DISEASE ; MALIGNANT BRAIN-TUMORS ; SCAVENGER RECEPTOR ; in situ hybridization ; CHAIN ; BRAIN-TUMORS ; pathogen ; VARIANT ; ALLELE ; inflammatory bowel disease ; LEVEL ; methods ; SUBTYPES ; SULFATE ; USA ; function ; INCREASED RISK ; odds ratio ; in vivo ; case control ; quantitative ; MUCOSAL ; EXONS ; CRP-DUCTIN ; DEXTRAN SULFATE SODIUM
    Abstract: Background & Aims: Impaired mucosal. defense plays an important role in the pathogenesis of Crohn's disease (CD), one of the main subtypes of inflammatory bowel disease (IBD). Deleted in malignant brain tumors 1(DMBT1) is a secreted scavenger receptor cysteine-rich protein with predominant expression in. the intestine and has been proposed to exert possible functions in regenerative processes and pathogen defense. Here, we aimed at analyzing the role of DMBT1 in IBD. Methods: We studied DMBT1 expression in IBD and normal tissues by quantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and mRNA in situ hybridization. Genetic polymorphisms within DMBT1 were analyzed in an Italian IBD case-control sample. Dmbt1(-/-) mice were generated, characterized, and analyzed for their susceptibility to dextran sulfate sodium-induced colitis. Results: DMBT1 levels correlate with disease activity in inflamed IBD tissues. A highly significant fraction of the patients with IBD displayed up-regulation of DMBT1 specifically in the intestinal epithelial surface cells and Paneth cells. A deletion allele of DMBT1 with a reduced: number of scavenger receptor cysteine-rich domain coding exons is associated with an increased risk of CD (P =.00056; odds ratio, 1.75) but not for ulcerative colitis. Dmbt1(-/-) mice display enhanced susceptibility to dextran sulfate sodium-induced colitis and elevated Tnf, Il6, and Nod2 expression levels during inflammation. Conclusions: DMBT1 may play a role in intestinal mucosal protection and prevention of inflammation. Impaired DMBT1 function may contribute to the pathogenesis of CD
    Type of Publication: Journal article published
    PubMed ID: 17983803
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; DEATH ; DISEASE ; SITES ; GENE ; GENE-EXPRESSION ; SAMPLES ; transcription ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; T cells ; T-CELL ; AMPLIFICATION ; immunohistochemistry ; gene expression ; ASSAY ; resistance ; INDUCED APOPTOSIS ; PATHOGENESIS ; EPITHELIAL-CELLS ; INVOLVEMENT ; KAPPA-B ; expression profiling ; microdissection ; ULCERATIVE-COLITIS ; inflammation ; INFLAMMATORY-BOWEL-DISEASE ; CANDIDATE GENES ; INTERCELLULAR-ADHESION MOLECULE-1 ; FAS LIGAND ; DYSFUNCTION ; POLYMERASE ; DEATH LIGAND ; MONOCYTE ADHESION
    Abstract: Aims: Both epithelial barrier dysfunction and apoptosis resistance of immune cells contribute to the pathogenesis of Crohn's disease. The soluble decoy receptor 3 (DcR3) acts in an anti-apoptotic manner by neutralising the death ligand CD95L. Here, we investigated the possible involvement of DcR3 in Crohn's disease. Methods: The epithelial fraction of human small intestinal mucosa samples was obtained by laser microdissection. Expression of DcR3 was examined by global gene expression profiling, quantitative reverse transcription polymerase chain reaction, immunoblot analysis, and immunohistochemistry. DcR3 concentrations in the serum of patients with Crohn's disease were measured by enzyme-linked immunosorbent assay. Apoptosis assays were performed to study the effects of DcR3 in intestinal epithelial cells and lamina propria T cells. Results: DcR3 is over-expressed in the epithelial layer of ileum specimens in patients with Crohn's disease, both at actively inflamed and non-active sites. DcR3 serum levels are significantly elevated in patients with active and non-active Crohn's disease as compared to healthy controls. The expression of DcR3 in intestinal epithelial cells is induced by tumour necrosis factor a. Increased DcR3 expression is associated with activation of nuclear factor kappa B (NF-kappa B) and results in protection of intestinal epithelial cells and lamina propria T cells from CD95L-induced apoptosis. Conclusions: DcR3 may promote inflammation in Crohn's disease by inhibiting CD95L-induced apoptosis of epithelial and immune cells as well as by inducing NF-kappa B activation
    Type of Publication: Journal article published
    PubMed ID: 19039087
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