The oxidase activity of vascular adhesion protein-1 (VAP-1) induces endothelial E- and P-selectins and leukocyte binding.
Leukocyte migration from the blood into tissues is pivotal in immune homeostasis and in inflammation. During the multistep extravasation cascade, endothelial selectins (P- and E-selectin) and vascular adhesion protein-1 (VAP-1), a cell-surface-expressed oxidase, are important in tethering and rolling. Here, we studied the signaling functions of the catalytic activity of VAP-1. Using human endothelial cells transfected with wild-type VAP-1 and an enzymatically inactive VAP-1 point mutant, we show that transcription and translation of E- and P-selectins are induced through the enzymatic activity of VAP-1. Moreover, use of VAP-1-deficient animals and VAP-1-deficient animals carrying the human VAP-1 as a transgene show a VAP-enzyme activity-dependent induction of P-selectin in vivo. Up-regulation of P-selectin was found both in high endothelial venules in lymphoid tissues and in flat-walled vessels in noninflamed tissues. VAP-1 activity in vivo led to increased P-selectin-dependent binding of lymphocytes to endothelial cells. These data show that the oxidase reaction catalyzed by VAP-1 alters the expression of other molecules involved in the leukocyte extravasation cascade. Our findings indicate cross-talk between adhesion molecules involved in the tethering and rolling of leukocytes and show that VAP-1-dependent signaling can prime the vessels for an enhanced inflammatory response.
Jalkanen
Sirpa
S
MediCity Research Laboratory, University of Turku, Turku, Finland.
Karikoski
Marika
M
Mercier
Nathalie
N
Koskinen
Kaisa
K
Henttinen
Tiina
T
Elima
Kati
K
Salmivirta
Katriina
K
Salmi
Marko
M
D006631:Amine Oxidase (Copper-Containing) / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019041:L-Selectin / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D008744:Methylamines / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016877:Oxidants / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
D015815:Cell Adhesion Molecules; D019040:E-Selectin; D008744:Methylamines; D016877:Oxidants; D012333:RNA, Messenger; D019041:L-Selectin; D006861:Hydrogen Peroxide; C027451:methylamine; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse