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Early-stage blocking of Notch signaling inhibits the depletion of goblet cells in dextran sodium sulfate-induced colitis in mice

  • Original Article—Alimentary Tract
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Abstract

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 μmol/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-1β 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.

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Abbreviations

DAI:

Disease activity index

DBZ:

Dibenzazepine

DSS:

Dextran sulfate sodium

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Acknowledgments

We are grateful to Dr. S. Kokura (Kyoto Prefectural University of Medicine, Kyoto, Japan) for helpful discussion. We also thank Dr. W. T. V. Germeraad (University Hospital Maastricht, Maastricht, The Netherlands) for his critical reading of the manuscript. This study was supported by a grant-in-aid of the Japanese Ministry of Education, Culture, Sports, Science and Technology.

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Author notes

  1. Reiko Ito

    Present address: Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan

Authors and Affiliations

  1. Department of Gastroenterology, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyoku, Kyoto, 602-8566, Japan

    Misumi Shinoda, Yuji Naito, Reiko Ito, Norihisa Suzuki, Hiroaki Yasuda, Junichi Sakagami, Keisho Kataoka & Toshikazu Yoshikawa

  2. Department of Microbiology, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kamigyoku, Kyoto, 602-8566, Japan

    Misumi Shinoda, Masaharu Shin-Ya, Tsunao Kishida, Reiko Ito, Jiro Imanishi & Osam Mazda

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  1. Misumi Shinoda
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Correspondence to Masaharu Shin-Ya or Osam Mazda.

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Shinoda, M., Shin-Ya, M., Naito, Y. et al. Early-stage blocking of Notch signaling inhibits the depletion of goblet cells in dextran sodium sulfate-induced colitis in mice. J Gastroenterol 45, 608–617 (2010). https://doi.org/10.1007/s00535-010-0210-z

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