Expression and regulation of the metalloproteinase ADAM-8 during human neutrophil pathophysiological activation and its catalytic activity on L-selectin shedding.
A disintegrin and metalloproteinase domain (ADAM) proteins are a family of transmembrane glycoproteins with heterogeneous expression profiles and proteolytic, cell-adhesion, -fusion, and -signaling properties. One of its members, ADAM-8, is expressed by several cell types including neurons, osteoclasts, and leukocytes and, although it has been implicated in osteoclastogenesis and neurodegenerative processes, little is known about its role in immune cells. In this study, we show that ADAM-8 is constitutively present both on the cell surface and in intracellular granules of human neutrophils. Upon in vitro neutrophil activation, ADAM-8 was mobilized from the granules to the plasma membrane, where it was released through a metalloproteinase-dependent shedding mechanism. Adhesion of resting neutrophils to human endothelial cells also led to up-regulation of ADAM-8 surface expression. Neutrophils isolated from the synovial fluid of patients with active rheumatoid arthritis expressed higher amounts of ADAM-8 than neutrophils isolated from peripheral blood and the concentration of soluble ADAM-8 in synovial fluid directly correlated with the degree of joint inflammation. Remarkably, the presence of ADAM-8 both on the cell surface and in suspension increased the ectodomain shedding of membrane-bound L-selectin in mammalian cells. All these data support a potential relevant role for ADAM-8 in the function of neutrophils during inflammatory response.
Gómez-Gaviro
Maria
M
Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
Domínguez-Luis
Maria
M
Canchado
Javier
J
Calafat
Jero
J
Janssen
Hans
H
Lara-Pezzi
Enrique
E
Fourie
Anne
A
Tugores
Antonio
A
Valenzuela-Fernández
Agustín
A
Mollinedo
Faustino
F
Sánchez-Madrid
Francisco
F
Díaz-González
Federico
F
D051722:ADAM Proteins / Q000032:analysis / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000276:immunology*; D002384:Catalysis; D002448:Cell Adhesion; D002462:Cell Membrane / Q000201:enzymology; D003594:Cytoplasmic Granules / Q000201:enzymology; D042783:Endothelial Cells / Q000276:immunology; D006801:Humans; D019041:L-Selectin / Q000378:metabolism*; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D045726:Metalloproteases / Q000032:analysis / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology*; D021381:Protein Transport; D013582:Synovial Fluid / Q000276:immunology; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D008565:Membrane Proteins; D019041:L-Selectin; D045726:Metalloproteases; D051722:ADAM Proteins; C068490:ADAM8 protein, human