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Blood, 7 May 2009, Vol. 113, No. 19, pp. 4799-4809. Prepublished online as a Blood First Edition Paper on March 3, 2009; DOI 10.1182/blood-2008-04-152330. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-04-152330v1 113/19/4799    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Koenen, R. R. Articles by Ludwig, A. Search for Related Content PubMed PubMed Citation Articles by Koenen, R. R. Articles by Ludwig, A. Related Collections Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  VASCULAR BIOLOGY Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases Rory R. Koenen1,*, Jessica Pruessmeyer2,3,*, Oliver Soehnlein1,4, Line Fraemohs1, Alma Zernecke1, Nicole Schwarz2, Karina Reiss5, Alisina Sarabi1, Lennart Lindbom4, Tilman M. Hackeng6, Christian Weber1,6, and Andreas Ludwig2,3 1 Institute for Molecular Cardiovascular Research, 2 Institute for Pharmacology and Toxicology, and 3 Interdisciplinary Center for Clinical Research Biomat, Medical Faculty, RWTH Aachen University, Aachen, Germany; 4 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; 5 Institute for Biochemistry, Christian-Albrechts-University, Kiel, Germany; and 6 Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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