Fig. 1. Localization of NF κB p65protein in the presence and the absence of Candesartan during TNF α stimulation. Cells were pretreated with or without Candesartan and then stimulated with TNF α. Immunofluorescent costaining of NF κB p65 protein and cell nuclei stained using DAPI was subsequently performed. Quoted from ref. 48. ration of colitis (Fig. 1).(48) It has also shown that there is a signifi- cant attenuation of MAdCAM-1 expression, inflammatory cell infiltration and mucosal damages during DSS-induced colitis in mice lacking AT1R gene compared to these parameters in wild- type mice.(48,49) This result suggests that TNF-α can induce MAdCAM-1 expression by three different pathways. Blocking the pathway by which TNF-α induces MAdCAM-1 expression is thus considered to be useful for IBD treatment. Several studies have been carried out to search for potent candidate blockers of TNF-α-induced MAdCAM-1 expression that could be used for IBD treatment. Such candidates include a component present in grapefruit and grapefruit peel oil, its deriva- tives; bergamottin and DHB,(47) CYP450 inhibitor, troglitazone,(50) which is a γ-subtype of a peroxisome proliferator-activated receptor (PPAR-γ) ligand that blocks phosphorylation of p65 NF-κB, and candesartan,(48) which, as mentioned above, is an agent that blocks translocation of the activated p50/p65 NF-κB complex into the nucleus. Conclusion and Perspectives It has been established that ROS and MAdCAM-1 play a critical role in the development of IBD by mediating enhanced extravasa- tion of lymphocytes. Future development and study of neutral- izing or blocking antibodies, and chemicals that target molecules involved in the development of IBD, (Table 1), will ensure that detailed molecular mechanisms that underlie the occurrence and perpetuation of gut inflammation will be elucidated in the future. Acknowledgments Satoshi Tanida, Tsutomu Mizoshita, Takashi Mizushima, 114 Takaya Shimura, Takeshi Kamiya and Hiromi Kataoka are all members of digestive disease group in Nagoya City University, Department of Gastroenterology and Metabolism and Professor Takashi Joh heads up our department. Makoto Sasaki is one of the members of digestive disease group in Aichi Medical University. We are going forward on the advanced basic researches in order to elucidate how persistent inflammation induces the occurrence of cancer, and how IBD inflammation occurs, and are trying to clarify these difficult problems in the future. Abbreviations IBD UC CD ROS ICAM-1 VCAM-1 MAdCAM-1 TNF IL NO RNM LPS Ig HEV LPAM DSS TNB NF-κB MAPKs inflammatory bowel diseases ulcerative colitis Crohn’s disease reactive oxygen species intercellular adhesion molecule 1 vascular cell adhesion molecule-1 mucosal addressin cell adhesion molecule-1 tumor necrotic factor interleukin nitric oxygen reactive nitrogen metabolites lipopolysaccharide immunoglobulin high endothelial venules lymphocyte Peyer’s patches HEV adhesion molecule dextran sulfate sodium trinitrobenzene sulfonic acid nuclear factor kappa-B mitogen-activated protein kinases doi: 10.3164/jcbn.1041 ©2011 JCBN