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Claudin-2 Regulates Colorectal Inflammation via Myosin Light Chain Kinase-Dependent Signaling

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Abstract

Background

Claudins have been demonstrated to be associated with inflammatory bowel disease (IBD), but the specific role of claudin-2 in colorectal inflammation remains undefined.

Aims

We aimed to determine the role of claudin-2 in TNFα-induced colorectal inflammation.

Methods

We used claudin-2 (−/−) mice to assess the role of claudin-2 in colon. The mice were intraperitoneally injected with 3 μg of recombinant murine TNFα, and the NF-κB signaling and mRNA expression levels of proinflammatory cytokines and myosin light chain kinase (MLCK) were evaluated. Moreover, in claudin-2 (−/−) mice, colitis was induced by the administration of dextran sodium sulfate (DSS). The involvement of claudin-2 in colorectal inflammation was also investigated using the Caco-2 human colon adenocarcinoma cell line, and the expression of claudin-2 was downregulated using claudin-2 siRNA.

Results

TNFα-induced colorectal inflammation via NF-κB signaling activation was enhanced in claudin-2 (−/−) mice compared with that in claudin-2 (+/+) mice. MLCK expression level in the colon tissue of claudin-2 (−/−) mice treated with TNFα was enhanced in comparison to that of the claudin-2 (+/+) mice. DSS-induced colitis was more severe in the claudin-2 (−/−) mice than in the claudin-2 (+/−) mice. In in vitro experiments, the decreased expression of claudin-2 enhanced the expressions of IL-6, IL-1β and MLCK.

Conclusions

Our findings concerning the role of claudin-2 in epithelial inflammatory responses enrich our collective understanding of mucosal homeostasis and intestinal diseases such as IBD. Furthermore, the results of this study indicate that claudin-2 and MLCK are potential therapeutic targets for treatments against intestinal disease.

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Acknowledgments

This study was supported by grants for the Global COE Program, Global Center of Excellence for Education and Research on Signal Transduction Medicine in the Coming Generation (M.Y. and T.A.), and for the Global COE Program, the Global Center for Education and Research in Integrative Membrane Biology (M.N.).

Conflict of interest

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Chu-o-ku, Kusunoki-Cho, Kobe, Hyogo, 650-0017, Japan

    Masayuki Nishida, Masaru Yoshida, Shin Nishiumi & Takeshi Azuma

  2. The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, 7-5-1 Chu-o-ku, Kusunoki-Cho, Kobe, Hyogo, 650-0017, Japan

    Masaru Yoshida

  3. Division of Metabolomics Research, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Chu-o-ku, Kusunoki-Cho, Kobe, Hyogo, 650-0017, Japan

    Masaru Yoshida

  4. Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Chu-o-ku, Kusunoki-Cho, Kobe, Hyogo, 650-0017, Japan

    Mikio Furuse

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  1. Masayuki Nishida
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  2. Masaru Yoshida
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  3. Shin Nishiumi
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Correspondence to Masaru Yoshida or Takeshi Azuma.

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Nishida, M., Yoshida, M., Nishiumi, S. et al. Claudin-2 Regulates Colorectal Inflammation via Myosin Light Chain Kinase-Dependent Signaling. Dig Dis Sci 58, 1546–1559 (2013). https://doi.org/10.1007/s10620-012-2535-3

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  • DOI: https://doi.org/10.1007/s10620-012-2535-3

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