Early-stage blocking of Notch signaling inhibits the depletion of goblet cells in dextran sodium sulfate-induced colitis in mice.
BACKGROUND
Goblet cells, which contribute to mucosal defense and repair in the intestinal epithelium, are depleted in human and rodent colitis. The Notch signal pathway regulates the differentiation of intestinal stem cells into epithelial cells and inhibits the differentiation of secretory lineages, including goblet cells. The aim of our study was to clarify whether the blocking of the Notch pathway at an early stage of colitis would preserve goblet cells and facilitate the healing process in dextran sulfate sodium (DSS)-induced colitis in mice.


METHODS
DSS was orally administered to C57/BL6 mice for 7 days, and dibenzazepine (DBZ), a Notch pathway blocker, was administered for 5 consecutive days, beginning on the first day of DSS treatment. Colonic mucosal inflammation was evaluated clinically, biochemically, and histologically. The expression of the goblet cell-associated genes Math1 and MUC2 and proinflammatory cytokines was evaluated by real-time reverse-transcriptase-PCR, with the expression of Math1 and MUC2 also visualized by immunohistochemical examination.


RESULTS
The administration of DBZ at 4 mumol/kg significantly reduced the severity of the colitis. Compared with the DSS only-treated intestine, the number of goblet cells was relatively sustained, and the expression of Math1 and MUC2 was also elevated in the DSS/DBZ-treated intestine. DBZ treatment suppressed the mRNA levels for interleukin-1beta and -6, and matrix metalloproteinases-3 and -9 in the DSS-treated intestine.


CONCLUSIONS
Early-stage blocking of Notch signaling may ameliorate acute DSS colitis by preventing reduction in the number of goblet cells.
Shinoda
Misumi
M
Department of Gastroenterology, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyoku, Kyoto, 602-8566, Japan.
Shin-Ya
Masaharu
M
Naito
Yuji
Y
Kishida
Tsunao
T
Ito
Reiko
R
Suzuki
Norihisa
N
Yasuda
Hiroaki
H
Sakagami
Junichi
J
Imanishi
Jiro
J
Kataoka
Keisho
K
Mazda
Osam
O
Yoshikawa
Toshikazu
T
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D003092:Colitis / Q000188:drug therapy* / Q000503:physiopathology; D016264:Dextran Sulfate / Q000633:toxicity; D003984:Dibenzazepines / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020397:Goblet Cells / Q000187:drug effects* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055262:Mucin-2 / Q000235:genetics; D051880:Receptors, Notch / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects
D051792:Basic Helix-Loop-Helix Proteins; D016264:Dextran Sulfate; D003984:Dibenzazepines; D055262:Mucin-2; D051880:Receptors, Notch; C500943:Atoh1 protein, mouse; C524626:Muc2 protein, mouse; C527817:dibenzazepine