Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases.
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.
Koenen
Rory R
RR
MedicalFaculty, Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany.
Pruessmeyer
Jessica
J
Soehnlein
Oliver
O
Fraemohs
Line
L
Zernecke
Alma
A
Schwarz
Nicole
N
Reiss
Karina
K
Sarabi
Alisina
A
Lindbom
Lennart
L
Hackeng
Tilman M
TM
Weber
Christian
C
Ludwig
Andreas
A
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology
D015815:Cell Adhesion Molecules; D016207:Cytokines; C407243:F11R protein, human; C498686:F11r protein, mouse; D007136:Immunoglobulins; D008565:Membrane Proteins; D011480:Protease Inhibitors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse