Abstract
Junctional adhesion molecule A (JAM-A) is a transmembrane adhesive glycoprotein that participates in the organization of endothelial tight junctions and contributes to leukocyte transendothelial migration. We demonstrate here that cultured endothelial cells not only express a cellular 43-kDa variant of JAM-A but also release considerable amounts of a 33-kDa soluble JAM-A variant. This release is enhanced by treatment with proinflammatory cytokines and is associated with the down-regulation of surface JAM-A. Inhibition experiments, loss/gain-of-function experiments, and cleavage experiments with recombinant proteases indicated that cleavage of JAM-A is mediated predominantly by the disintegrin and metalloproteinase (ADAM) 17 and, to a lesser extent, by ADAM10. Cytokine treatment of mice increased JAM-A serum level and in excised murine aortas increased ADAM10/17 activity correlated with enhanced JAM-A release. Functionally, soluble JAM-A blocked migration of cultured endothelial cells, reduced transendothelial migration of isolated neutrophils in vitro, and decreased neutrophil infiltration in a murine air pouch model by LFA-1- and JAM-A-dependent mechanisms. Therefore, shedding of JAM-A by inflamed vascular endothelium via ADAM17 and ADAM10 may not only generate a biomarker for vascular inflammation but could also be instrumental in controlling JAM-A functions in the molecular zipper guiding transendothelial diapedesis of leukocytes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / antagonists & inhibitors
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ADAM Proteins / physiology*
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ADAM10 Protein
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ADAM17 Protein
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / physiology*
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Animals
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Aorta / cytology
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Aorta / metabolism
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Blotting, Western
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Cell Adhesion / physiology
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism*
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Cell Adhesion Molecules / physiology*
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Cells, Cultured
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Cytokines / metabolism
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism
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Enzyme-Linked Immunosorbent Assay
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Humans
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Immunoenzyme Techniques
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Immunoglobulins / genetics
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Immunoglobulins / metabolism*
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Kidney / cytology
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Kidney / metabolism
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Male
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neutrophils / metabolism
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Protease Inhibitors / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Cell Surface / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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Umbilical Veins / cytology
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Umbilical Veins / metabolism
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Urinary Bladder Neoplasms / metabolism
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Urinary Bladder Neoplasms / pathology
Substances
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Cell Adhesion Molecules
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Cytokines
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F11R protein, human
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F11r protein, mouse
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Immunoglobulins
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Membrane Proteins
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Protease Inhibitors
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RNA, Messenger
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Receptors, Cell Surface
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Amyloid Precursor Protein Secretases
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ADAM Proteins
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ADAM10 Protein
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Adam10 protein, mouse
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, mouse