Activation of vascular adhesion protein-1 on liver endothelium results in an NF-kappaB-dependent increase in lymphocyte adhesion.

UNLABELLED: Vascular adhesion protein-1 (VAP-1) is an adhesion molecule and amine oxidase that is expressed at high levels in the human liver. It promotes leukocyte adhesion to the liver in vivo and drives lymphocyte transmigration across hepatic sinusoidal endothelial cells in vitro. We report that in addition to supporting leukocyte adhesion, provision of specific substrate to VAP-1 results in hepatic endothelial cell activation, which can be abrogated by treatment with the enzyme inhibitor semicarbazide. VAP-1-mediated activation was rapid; dependent upon nuclear factor-kappaB, phosphatidylinositol-3 kinase, and mitogen-activated protein kinase pathways; and led to upregulation of the adhesion molecules E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and secretion of the chemokine CXCL8. This response resulted in enhanced lymphocyte adhesion, was restricted to hepatic endothelial cells that expressed VAP-1, and was not observed in human umbilical vein endothelial cells. CONCLUSION: We propose that as well as directly promoting adhesion via interactions with the as yet unknown ligand, binding of enzyme substrate to VAP-1 can indirectly promote inflammatory cell recruitment via upregulation of adhesion molecules and chemokines. This response is likely to be important for the recruitment of leukocytes to the liver and suggests that VAP-1 inhibitors have therapeutic potential for treating chronic inflammatory liver disease.

Expression of DC-SIGN and DC-SIGNR on human sinusoidal endothelium: a role for capturing hepatitis C virus particles.

Hepatic sinusoidal endothelial cells are unique among endothelial cells in their ability to internalize and process a diverse range of antigens. DC-SIGNR, a type 2 C-type lectin expressed on liver sinusoids, has been shown to bind with high affinity to hepatitis C virus (HCV) E2 glycoprotein. DC-SIGN is a closely related homologue reported to be expressed only on dendritic cells and a subset of macrophages and has similar binding affinity to HCV E2 glycoprotein. These receptors function as adhesion and antigen presentation molecules. We report distinct patterns of DC-SIGNR and DC-SIGN expression in human liver tissue and show for the first time that both C-type lectins are expressed on sinusoidal endothelial cells. We confirmed that these receptors are functional by demonstrating their ability to bind HCV E2 glycoproteins. Although these lectins on primary sinusoidal cells support HCV E2 binding, they are unable to support HCV entry. These data support a model where DC-SIGN and DC-SIGNR on sinusoidal endothelium provide a mechanism for high affinity binding of circulating HCV within the liver sinusoids allowing subsequent transfer of the virus to underlying hepatocytes, in a manner analogous to DC-SIGN presentation of human immunodeficiency virus on dendritic cells.