membranes, and, despite a relatively short half-life (within 10 ms), it can interact with target molecules in an adjacent cell within one or two cell diameters.(9) Interestingly, exposure to ONOO– pro- motes the conversion of tyrosine residues into 3-nitrotyrosine, which cannot be readily phosphorylated. ONOO– thus interferes with cellular signaling that is dependent on tyrosine phosphoryla- tion by protein tyrosine kinases.(10) Tyrosine nitration by ONOO– can either prevent a protein from functioning as the phosphory- lated form and/or can mimic the structural change induced by phosphorylation and thereby imitate the consequences of phos- phorylation.(11) In contrast to OH, ONOO– can up- or down- regulate signaling cascades by controlling the activities of protein kinases. This control is achieved by nitration of tyrosine residues, thereby resulting in gain- or loss of function of kinase activity.(12) Finally, regarding the effect of ROS on DNA, both nuclear DNA(13) and mitochondrial DNA(14) are also known to be targets of oxidative attack, particularly from OH and ONOO–, which cause base and sugar hydroxylation(15) as well as breaks in the double strand, leading to adenosine triphosphate depletion, gene mutations and mitochondrial DNA deletions.(16,17) These changes ultimately induce malignant transformation and apoptotic cell death. Thus, oxidative stress thus harms almost all cellular components. Noxious Involvement of ROS in IBD Direct measurement of ROS in cells and tissues is quite difficult because of their short biological half-lives.(18) However, direct quantification of ROS levels in colon biopsy specimens from UC and CD patients using chemiluminescence assays showed that ROS levels in these tissues are considerably increased compared to those in normal mucosa and positively correlate with IBD.(19–22) Mounting evidences indicate that there are increased levels of reactive nitrogen metabolites (RNM) such as NO in the inflamed IBD mucosa based on analysis of nitric oxide synthase activity.(23–26) Thus, increased levels of both ROS and RNM are closely corre- lated with the clinical development of IBD. Relationship between Adhesive Molecules and Cytokines, and Inflammatory Cells Infiltration and Immune Responses The consecutive events involved in the extravasation of inflam- matory cells from lymphatics and blood vessels to the extra- vascular space include the following steps: 1, tethering and rolling of the inflammatory cells on the endothelial cell surface; 2, firm attachment to endothelial cells followed by transendothelial migration; and 3, migration toward chemoattractants produced in the lamina propria, which is mediated by the interaction between adhesion molecules on the surface of lymphocytes or neutrophils and their receptors on endothelial cells and vice versa. Various cytokines induce the tethering and rolling of neutrophils on vascular endothelial cells through modulation of the interactions between L-selectin and carbohydrate antigen on neutrophils, and P- and E-selectin on endothelial cells.(27–29) On the other hand interactions between adhesion molecules on the surface of lym- phocytes and the adhesion molecule MAdCAM-1 on lymphatic endothelial cells are responsible for lymphocyte tethering.(30) At a later stage, neutrophils and lymphocytes strongly adhere to endo- thelial cells through other adhesion molecules including ICAM-1, VCAM-1 and MAdCAM-1, and consequently transmigrate into lamina propria mucosae. ROS, lipopolysaccharide (LPS) and inflammatory cytokines such as IL-1β and TNF-α induce the translocation of P-selectin, L-selectin and MAdCAM-1 from intracellular locations to the cell surface. Increased surface expres- sion of P-selectin, ICAM, and MAdCAM-1 is observed in the colon mucosa of patients with IBD.(31,32) Interaction between inflammatory cells and endothelial cells through these adhesion molecules is thus involved in the development of IBD. S. Tanida et al. MAdCAM1 and Its Receptor, α4β7 Integrin MAdCAM-1 is a 58–66 kDa type 1 transmembrane glyco- protein belonging to the immunoglobulin (Ig) superfamily, which is comprised of two amino-terminal Ig-like domains and shares a conserved amino acid sequence homology with VCAM-1.(33) The interaction of integrin α4β7 and MAdCAM-1 is involved in cell homing, firm adhesion, and transendothelial cell migration when lymphocytes are recirculated to peripheral lymph nodes under normal conditions and when lymphocytes are recruited to sites of gut inflammation.(30) The homing of murine lymphocytes to intestinal mucosa was first discovered to be mediated by a molecule that bound to Peyer’s patches high endothelial venules (HEV).(34) This molecule is known as lymphocyte Peyer’s patches HEV adhesion molecule (LPAM)-1 and was ultimately identified as an integrin, which is a heterodimer of α- and β-subunits. The α4- subunit of murine LPAM-2 has 84% homology at the amino acid level with the human integrin α4-subunit.(35) An anti-rat α4 blocking antibody inhibited lymphocyte migration to Peyer’s patches, indicating that α4 integrin plays an important role in mucosal homing.(36) Initially, the murine integrin β-subunit was believed to be a novel molecule. However, it is currently known that the human β7 integrin subunit is the human homolog of the murine integrin β- subunit.(37,38) MAdCAM-1 is expressed in Peyer’s patches HEV and in mesenteric lymph nodes, intestinal mucosal venules in the lamina propria, and lymphoid follicles in the normal murine gut. MAdCAM-1 directly binds to its receptor, α4β7 integrin. Blocking antibodies against either α4- or β7-subunits abrogate the binding of lymphocytes to MAdCAM-1 in vivo and in vitro.(39) Therefore, MAdCAM-1 binds to both α4- and β7-subunits. IBD and MAdCAM1 Under normal conditions, MAdCAM-1 expression is limited to the endothelium of venules within the lamina propria and submucosa, and to the HEVs of Peyer’s patches and mesenteric lymph nodes. In mouse models of IBD in which experimental colitis was induced with dextran sulfate sodium (DSS) or trinitro- benzene sulfonic acid (TNB), and also in the inflamed colon of human patients with UC and CD, MAdCAM-1 expression was reported to be increased in the lamina propria and submucosal venules within the inflamed sites of the colon compared to its expression in non-inflamed tissues.(40–42) MAdCAM-1 transcrip- tion is activated through translocation of the activated p50/p65 nuclear factor kappa-B (NF-κB) complex into the nucleus following proteosomal degradation of phosphorylated IκB (inhibitor of κB) in response to several cytokines including TNF-α and IL-1β.(43,44) Moreover, experimental studies using a SVEC cell line derived from axillary lymph nodes, and a colon-derived endothelial cell line established from transgenic mice bearing a temperature-sensitive SV40 large T antigen, have shown that TNF-α stimulates MAdCAM-1 expression through activation of tyrosine kinase, p38 and p42/p44 mitogen-activated protein kinase (MAPK), and NF-κB/poly-ADP ribose polymerase (PARP) signaling cascades.(45,46) The addition of cytochrome P-450 (CYP450) 3A4 inhibitors such as bergamottin and 6',7'-dihydroxybergamottin (DHB) to cultured SVEC endothelial cells demonstrated that these CYP450 inhibitors blocked TNF-α-induced MAdCAM-1 expression and lymphocyte adhesion in vitro.(47) Interestingly, our very recent study showed that the angiotensin II type 1 receptor antagonist (AT1R antagonist), candesartan, can be used as a novel therapy for IBD. We demonstrated that this AT1R antagonist blocked intranuclear translocation of the activated p50/p65 NF-κB complex in a p38 MAPK independent manner and thereby downregulated TNF-α-induced MAdCAM-1 expression, resulting in the amelio- J. Clin. Biochem. Nutr. | March 2011 | vol. 48 | no. 2 | 113 ©2011 JCBN