title: Human vascular adhesion protein-1 (VAP-1) plays a critical role in lymphocyte-endothelial cell adhesion cascade under shear.
abstract: Lymphocyte binding to vascular endothelium is a prerequisite for the movement of immune cells from the blood into lymphoid tissues and into sites of inflammation. Human vascular adhesion protein-1 (VAP-1) is an endothelial glycoprotein involved in this interaction. It also displays an enzymatic (monoamine oxidase) activity. Here we examined how recombinant human VAP-1 mediates lymphocyte binding using rotatory and flow chamber binding assays. VAP-1 cDNA transfected into an endothelial cell line, which does not bind lymphocytes, renders the cell line capable of binding lymphocytes in a shear-dependent manner. VAP-1 transfectants bound lymphocytes 5 times better than monocytes with a preference for T killer cells, and no specific granulocyte adherence was detectable. The binding is partially inhibited by anti-VAP-1 monoclonal antibodies or by blocking lymphocyte L-selectin and CD18 integrins, but not by inhibition of several other homing-associated molecules. In contrast, CD44 ligation on lymphocytes markedly upregulates their VAP-1-dependent adhesion, suggesting that the VAP-1 counterreceptor can be activated via CD44. The transfectant model also allowed us to perform detailed structure-function analyses of VAP-1. We show that the exposed integrin-binding motif RGD or the enzymatic activity is not indispensable for VAP-1-dependent adhesion. Together, these data show that VAP-1 can reconstitute the lymphocyte-endothelial adhesion cascade under shear and propose a critical role for VAP-1 in lymphocyte emigration from the blood.
authors.affiliation: MediCity Research Laboratory, University of Turku, and National Public Health Institute, Department in Turku, Turku, Finland. marko.salmi@utu.fi
authors.forename: M
authors.initials: M
authors.lastname: Salmi
authors.forename: S
authors.initials: S
authors.lastname: Tohka
authors.forename: S
authors.initials: S
authors.lastname: Jalkanen
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000595:Amino Acid Sequence / Q000235:genetics / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology; D019041:L-Selectin / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D016131:Lymphocyte Subsets / Q000502:physiology; D008214:Lymphocytes / Q000502:physiology*; D013314:Stress, Mechanical; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D018960:Hyaluronan Receptors; D016169:Lymphocyte Function-Associated Antigen-1; D019041:L-Selectin; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing)