title: Claudin-2 regulates colorectal inflammation via myosin light chain kinase-dependent signaling.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: 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@med.kobe-u.ac.jp
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nishida
authors.forename: Masaru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Shin
authors.initials: S
authors.lastname: Nishiumi
authors.forename: Mikio
authors.initials: M
authors.lastname: Furuse
authors.forename: Takeshi
authors.initials: T
authors.lastname: Azuma
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D018938:Caco-2 Cells; D062446:Claudin-2 / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011349:Proctitis / Q000139:chemically induced / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha
chemical_list: D015415:Biomarkers; D062446:Claudin-2; D016207:Cytokines; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D009219:Myosin-Light-Chain Kinase