Colonic gene expression patterns of mucin muc2 knockout mice reveal various phases in colitis development

Authors


  • Supported by Sophia Foundation for Scientific Research (SSWO Projects nos. 559 and 629), Erasmus MC, Rotterdam, the Netherlands, Stichting Willem H. Kröger, Rotterdam, the Netherlands, and l'Association François Aupetit, Paris, France.

Abstract

Background:

Mucin Muc2 knockout (Muc2−/−) mice spontaneously develop colitis.

Methods:

To identify genes and biological responses which play a pivotal role during colitis development in Muc2−/− mice, gene expression profiles of colonic tissues from 2- and 4-week-old Muc2−/− and wildtype mice were determined using microarrays.

Results:

The majority of highly upregulated genes in 2-week-old as well as 4-week-old Muc2−/− mice were primarily involved in immune responses related to antigen processing/presentation, B-cell and T-cell receptor signaling, leukocyte transendothelial migration, and Jak-STAT signaling. Specifically, Muc2−/− mice expressed high levels of immunoglobulins, murine histocompatibility-2, proinflammatory cytokines, chemokines, and antimicrobial proteins. Additionally, in 4-week-old Muc2−/− mice, expression of genes involved in cell structure related pathways was significantly altered. Particularly, the tight junction-associated gene claudin-10 was upregulated, whereas claudin-1 and claudin-5 were downregulated. Furthermore, 4-week-old Muc2−/− mice showed increased expression of genes regulating cell growth in conjunction with increased crypt length and increased epithelial proliferation.

Conclusions:

Muc2-deficiency leads to an active inflammatory response in 2- and 4-week-old Muc2−/− mice as demonstrated by the altered expression in immune response related genes. In addition, 4-week-old Muc2−/− mice also showed a decrease in epithelial barrier function and an increase in epithelial proliferation as indicated by, respectively, the altered expression in tight junction-related genes and upregulation of genes stimulating cell growth. Remarkably, upregulation of genes stimulating cell growth correlated with increased crypt length and increased epithelial proliferation in 4-week-old Muc2−/− mice. Together, these data demonstrate that there are distinct phases in colitis development in 2–4-week-old Muc2−/− mice. (Inflamm Bowel Dis 2011;)

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