Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases.
نویسندگان
چکیده
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.
منابع مشابه
VASCULAR BIOLOGY Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases
1Institute for Molecular Cardiovascular Research, 2Institute for Pharmacology and Toxicology, and 3Interdisciplinary Center for Clinical Research Biomat, Medical Faculty, RWTH Aachen University, Aachen, Germany; 4Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; 5Institute for Biochemistry, Christian-Albrechts-University, Kiel, Germany; and 6Cardiovascular Res...
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عنوان ژورنال:
- Blood
دوره 113 19 شماره
صفحات -
تاریخ انتشار 2009