title: Regulation of DMBT1 via NOD2 and TLR4 in intestinal epithelial cells modulates bacterial recognition and invasion.
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-kappaB 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-kappaB 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.
authors.affiliation: Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrache 12, Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Christian
authors.initials: C
authors.lastname: Sina
authors.forename: Caroline
authors.initials: C
authors.lastname: End
authors.forename: Marcus
authors.initials: M
authors.lastname: Renner
authors.forename: Stefan
authors.initials: S
authors.lastname: Lyer
authors.forename: Andreas
authors.initials: A
authors.lastname: Till
authors.forename: Stephan
authors.initials: S
authors.lastname: Hellmig
authors.forename: Susanna
authors.initials: S
authors.lastname: Nikolaus
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Fölsch
authors.forename: Burkhard
authors.initials: B
authors.lastname: Helmke
authors.forename: Frank
authors.initials: F
authors.lastname: Autschbach
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Petra
authors.initials: P
authors.lastname: Kioschis
authors.forename: Mathias
authors.initials: M
authors.lastname: Hafner
authors.forename: Annemarie
authors.initials: A
authors.lastname: Poustka
authors.forename: Jan
authors.initials: J
authors.lastname: Mollenhauer
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
mesh_terms: D002135:Calcium-Binding Proteins; D002460:Cell Line; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins; D005838:Genotype; D006801:Humans; D007413:Intestinal Mucosa / Q000737:chemistry / Q000276:immunology* / Q000382:microbiology; D008070:Lipopolysaccharides / Q000276:immunology; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D019779:Salmonella enterica / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
chemical_list: D002135:Calcium-Binding Proteins; C108174:DMBT1 protein, human; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins