Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease.
Loss of intestinal mucosa integrity is an important factor in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to characterize expression changes and allelic variants of genes related to intestinal epithelial barrier function in this disease. Therefore, ileal and colonic mucosal biopsies from nonaffected regions of patients with ulcerative colitis (UC) and Crohn's disease (CD), as well as non-IBD probands, were subjected to Affymetrix DNA-microarray analysis. Real-time reverse transcription polymerase chain reaction was used for verification in larger IBD sample numbers. Disturbed mRNA expression was identified for several mucin genes in both disease groups and tissues. A significant downregulation in the colon was obtained for MUC2 in CD and MUC12 in CD and UC. Expression analysis of all dysregulated mucins in a broad human tissue panel revealed dominant epithelial tissue-specific transcription. In silico analysis of the regulatory regions of these mucins indicated nuclear factor kappaB (NFkappaB) binding sites in each promoter. Furthermore, NFkappaB was overrepresented in mucin promoters and a component of a specific combination of transcription factors (composite module). In vivo stimulation experiments in the adenocarcinoma cell line LS174T showed inducible mucin expression by the cytokines tumor necrosis factor-alpha and transforming growth factor-beta, which could be blocked by NFkappaB signaling inhibitors. Allelic discrimination screening obtained statistically significant associations for the MUC2-V116M (P = 0.003) polymorphism with CD and for MUC4-A585S (P = 0.025), as well as MUC13-R502S (P = 0.0003) with UC. These data suggest that the disturbed expression of mucin genes and the connection to the NFkappaB pathway may influence the integrity of the intestine and therefore contribute to the pathophysiology of IBD.
Moehle
Christoph
C
Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsklinikum Regensburg, Franz-Josef-Strauss-Allee 11, 93042, Regensburg, Germany.
Ackermann
Nikolaus
N
Langmann
Thomas
T
Aslanidis
Charalampos
C
Kel
Alexander
A
Kel-Margoulis
Olga
O
Schmitz-Madry
Anna
A
Zahn
Alexandra
A
Stremmel
Wolfgang
W
Schmitz
Gerd
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D001706:Biopsy; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000473:pathology / Q000601:surgery; D003424:Crohn Disease / Q000473:pathology / Q000601:surgery; D005260:Female; D020869:Gene Expression Profiling; D014644:Genetic Variation; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000601:surgery; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D055262:Mucin-2; D055264:Mucin-4; D009077:Mucins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid
C429552:MUC13 protein, human; C524625:MUC2 protein, human; C524658:MUC4 protein, human; D055262:Mucin-2; D055264:Mucin-4; D009077:Mucins; D012333:RNA, Messenger