Masayuki Nishida1, Masaru Yoshida, Shin Nishiumi, Mikio Furuse, Takeshi Azuma. 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@med.kobe-u.ac.jp
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.
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 humancolon 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: M D Baugh; M J Perry; A P Hollander; D R Davies; S S Cross; A J Lobo; C J Taylor; G S Evans Journal: Gastroenterology Date: 1999-10 Impact factor: 22.682
Authors: Nicolas Montalbetti; Anna C Rued; Dennis R Clayton; Wily G Ruiz; Sheldon I Bastacky; H Sandeep Prakasam; Amity F Eaton; F Aura Kullmann; Gerard Apodaca; Marcelo D Carattino Journal: Am J Physiol Renal Physiol Date: 2015-09-30