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Claudin-2 regulates colorectal inflammation via myosin light chain kinase-dependent signaling
Masayuki Nishida1, Masaru Yoshida, Shin Nishiumi
1Division 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@med.kobe-u.ac.jp
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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