Regulation of DMBT1 via NOD2 and TLR4 in intestinal epithelial cells modulates bacterial recognition and invasion.
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.
Rosenstiel
Philip
P
Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrache 12, Kiel, Germany.
Sina
Christian
C
End
Caroline
C
Renner
Marcus
M
Lyer
Stefan
S
Till
Andreas
A
Hellmig
Stephan
S
Nikolaus
Susanna
S
Fölsch
Ulrich R
UR
Helmke
Burkhard
B
Autschbach
Frank
F
Schirmacher
Peter
P
Kioschis
Petra
P
Hafner
Mathias
M
Poustka
Annemarie
A
Mollenhauer
Jan
J
Schreiber
Stefan
S
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
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