6A,B). The importance of VAP-1/SSAO in this induction was confirmed by studies showing reduced MAdCAM-1 mRNA induction in mice expressing the enzymatically inactive form of hVAP-1 (Fig. 6B). Therefore, these data demonstrate the ability of VAP-1 enzyme activity to induce MAdCAM-1 expression in gut mucosal vessels in vivo. The ability of aberrantly expressed hepatic MAdCAM-1 to recruit mucosal T cells to the liver in patients with PSC9, 10 led us to further investigate factors involved in hepatic MAdCAM-1 induction. In this study, we provide evidence that VAP-1/SSAO–dependent oxidation of MA increases MAdCAM-1 expression in HECs in vitro and ex vivo

and in mucosal vessels in vivo. These findings http://www.selleckchem.com/products/epz-6438.html implicate VAP-1/SSAO activity in inducing and maintaining MAdCAM-1 expression in the gut and the liver. Although provision of the VAP-1 substrate MA or TNF-α led to induction of MAdCAM-1, the combination of the stimuli had an additive effect. The role of TNF-α in MAdCAM-1 induction has been reported previously in both AG-014699 clinical trial in vitro and in vivo systems.18-20 However, it is unlikely that TNF-α alone is sufficient to induce hepatic MAdCAM-1 in vivo

because hepatic MAdCAM-1 expression is limited, with the strongest and most consistent expression seen in patients with PSC or AIH complicating IBD.10 This led us to look for other factors that may have a particular role in the liver. VAP-1 is constitutively expressed in the human liver, and we have previously reported that the enzymatic activity of VAP-1 generates products (including H2O2) that can activate NF-κB–dependent adhesion molecule expression.17 This led us to hypothesize that the VAP-1/SSAO enzymatic activity could also promote MAdCAM-1 expression. We now confirm that this is the case, and we further demonstrate that the natural VAP-1/SSAO MCE公司 substrate MA, which is present in food, wine, and cigarette smoke, is able to increase MAdCAM-1 expression in vitro, in vivo, and ex vivo. Human HECs exposed to TNF-α and MA showed increased MAdCAM-1 mRNA transcription, protein redistribution onto the cell surface, and increased

secretion of the sMAdCAM-1 protein. Using flow-based adhesion assays, we confirmed that MA/TNF-α–induced MAdCAM-1 on HECs was functionally active and able to support increased adhesion of α4β7-expressing JY cells. There was residual binding of JY cells after MAdCAM-1 or α4β7 blocking, which we believe was mediated by lymphocyte function-associated antigen 1/ICAM-1. We also found that TNF-α and MA stimulation induced the production of a soluble form of MAdCAM-1. Leung et al.26 first reported sMAdCAM-1 in human serum, urine, and other biological fluids, but it is not known whether this soluble form is functional. Soluble forms of other adhesion molecules, including E-selectin and VAP-1, have the ability to enhance adhesion to endothelium.