Matrix metalloproteinase-9 regulates MUC-2 expression through its effect on goblet cell differentiation.
OBJECTIVE
We recently demonstrated that epithelial-derived matrix metalloproteinase (MMP) 9 up-regulated during inflammatory bowel disease is a critical mediator of tissue damage during colitis. MMP-9 null mice (MMP-9(-/-)) develop dramatically reduced inflammatory response to luminally administered colitic agents in the face of intact systemic immune response and inflammatory cell recruitment, suggesting protected epithelial barrier in these mice. In this study, we sought to address the role and mechanism by which MMP-9 influences barrier protective function.


METHODS
Wild-type and MMP-9(-/-) mice were used for in vivo studies, and the goblet cell line HT29-cl.16E and the enterocyte cell line Caco2-BBE were used for in vitro studies.


RESULTS
Compared with wild-type mice, MMP-9(-/-) mice had an increased number of goblet cells and MUC-2 expression. In addition, KLF-4 and Elf-3, transcription factors involved in terminal differentiation of goblet cells were up-regulated, whereas notch intracellular domain (NICD; activated Notch-1) was down-regulated in MMP-9(-/-) mice. These findings suggest altered epithelial cell differentiation in MMP-9(-/-) mice. Temporal expression of MMP-9 inversely correlated with MUC-2 expression during maturation of goblet cells. MMP-9 over expression inhibited goblet cell differentiation in vitro. Conversely, MMP-9 gene silencing in Caco2-BBE cells resulted in a change in their phenotype toward goblet cells. Finally, MMP-9 over expression or silencing in goblet cells increased or decreased Salmonella typhimurium adherence, respectively.


CONCLUSIONS
MMP-9 regulates goblet cell differentiation in colon. The effect of MMP-9 on goblet cells could contribute to alteration in mucosal defense leading to inflammation. Together, our data uncover a novel function of MMP-9 in intestinal epithelial cells.
Garg
Pallavi
P
Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
Ravi
Anupama
A
Patel
Neal R
NR
Roman
Jesse
J
Gewirtz
Andrew T
AT
Merlin
Didier
D
Sitaraman
Shanthi V
SV
D000818:Animals; D001422:Bacterial Adhesion / Q000502:physiology; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004198:Disease Susceptibility; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D020397:Goblet Cells / Q000166:cytology / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055262:Mucin-2; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012480:Salmonella Infections / Q000503:physiopathology / Q000517:prevention & control; D012486:Salmonella typhimurium / Q000472:pathogenicity; D014162:Transfection
C524625:MUC2 protein, human; C524626:Muc2 protein, mouse; D055262:Mucin-2; D009077:Mucins; D012333:RNA, Messenger; D020780:Matrix Metalloproteinase 9