| First Author | Mizushima T | Year | 2010 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 298 |
| Issue | 2 | Pages | G255-66 |
| PubMed ID | 19940029 | Mgi Jnum | J:157478 |
| Mgi Id | MGI:4430956 | Doi | 10.1152/ajpgi.00264.2009 |
| Citation | Mizushima T, et al. (2010) Blockage of angiotensin II type 1 receptor regulates TNF-alpha-induced MAdCAM-1 expression via inhibition of NF-kappaB translocation to the nucleus and ameliorates colitis. Am J Physiol Gastrointest Liver Physiol 298(2):G255-66 |
| abstractText | Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is an important target in the treatment of inflammatory bowel disease (IBD). Recently, treatment of IBD with an antibody to alpha4beta7-integrin, a ligand for MAdCAM-1, has been an intense focus of research. Our aim was to clarify the mechanism by which MAdCAM-1 is regulated via angiotensin II type 1 receptor (AT1R), and to verify if AT1R might be a novel target for IBD treatment. The role of AT1R in the expression of MAdCAM-1 in SVEC (a murine high endothelial venule cell) and MJC-1 (a mouse colonic endothelial cell) was examined following cytokine stimulation. We further evaluated the effect of AT1R on the pathogenesis of immune-mediated colitis using AT1R-deficient (AT1R-/-) mice and a selective AT1R blocker. AT1R blocker significantly suppressed MAdCAM-1 expression induced by TNF-alpha, but did not inhibit phosphorylation of p38 MAPK or of IkappaB that modulate MAdCAM-1 expression. However, NF-kappaB translocation into the nucleus was inhibited by these treatments. In a murine colitis model induced by dextran sulfate sodium, the degree of colitis, judged by body weight loss, histological damage, and the disease activity index, was much milder in AT1R-/- than in wild-type mice. The expression of MAdCAM-1 was also significantly lower in AT1R-/- than in wild-type mice. These results suggest that AT1R regulates the expression of MAdCAM-1 under colonic inflammatory conditions through regulation of the translocation of NF-kappaB into the nucleus. Furthermore, inhibition of AT1R ameliorates colitis in a mouse colitis model. Therefore, AT1R might be one of new therapeutic target of IBD via regulation of MAdCAM-1. |
