DMBT1 confers mucosal protection in vivo and a deletion variant is associated with Crohn's disease.
OBJECTIVE
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.
Renner
Marcus
M
Division of Molecular Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Bergmann
Gaby
G
Krebs
Inge
I
End
Caroline
C
Lyer
Stefan
S
Hilberg
Frank
F
Helmke
Burkhard
B
Gassler
Nikolaus
N
Autschbach
Frank
F
Bikker
Floris
F
Strobel-Freidekind
Olga
O
Gronert-Sum
Sabine
S
Benner
Axel
A
Blaich
Stephanie
S
Wittig
Rainer
R
Hudler
Melanie
M
Ligtenberg
Antoon J
AJ
Madsen
Jens
J
Holmskov
Uffe
U
Annese
Vito
V
Latiano
Anna
A
Schirmacher
Peter
P
Amerongen
Arie V Nieuw
AV
D'Amato
Mauro
M
Kioschis
Petra
P
Hafner
Mathias
M
Poustka
Annemarie
A
Mollenhauer
Jan
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D002648:Child; D003424:Crohn Disease / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology*; D004268:DNA-Binding Proteins; D016264:Dextran Sulfate; D004198:Disease Susceptibility; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009077:Mucins / Q000235:genetics / Q000502:physiology; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology*; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000235:genetics
D002135:Calcium-Binding Proteins; C108174:DMBT1 protein, human; D004268:DNA-Binding Proteins; C114202:Dmbt1 protein, mouse; D015850:Interleukin-6; D009077:Mucins; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D016264:Dextran Sulfate