title: 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.
abstract: 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.
authors: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Takashi
authors: T
authors: Mizushima
authors: Makoto
authors: M
authors: Sasaki
authors: Tomoaki
authors: T
authors: Ando
authors: Tsuneya
authors: T
authors: Wada
authors: Mamoru
authors: M
authors: Tanaka
authors: Yasuyuki
authors: Y
authors: Okamoto
authors: Masahide
authors: M
authors: Ebi
authors: Yosikazu
authors: Y
authors: Hirata
authors: Kenji
authors: K
authors: Murakami
authors: Tsutomu
authors: T
authors: Mizoshita
authors: Takaya
authors: T
authors: Shimura
authors: Eiji
authors: E
authors: Kubota
authors: Naotaka
authors: N
authors: Ogasawara
authors: Satoshi
authors: S
authors: Tanida
authors: Hiromi
authors: H
authors: Kataoka
authors: Takeshi
authors: T
authors: Kamiya
authors: J S
authors: JS
authors: Alexander
authors: Takashi
authors: T
authors: Joh
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics; D003092:Colitis / Q000378:metabolism* / Q000503:physiopathology; D003106:Colon / Q000098:blood supply; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009088:Mucoproteins; D016328:NF-kappa B / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D014699:Venules / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C491768:Ccl2 protein, mouse; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D020672:I-kappa B Proteins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases; C081643:candesartan