Print Email Facebook Twitter Degradation of tissue-type plasminogen activator by human monocyte- derived macrophages is mediated by the mannose receptor and by the low- density lipoprotein receptor-related protein Title Degradation of tissue-type plasminogen activator by human monocyte- derived macrophages is mediated by the mannose receptor and by the low- density lipoprotein receptor-related protein Author Noorman, F. Braat, E.A.M. Rijken, D.C. TNO Preventie en Gezondheid Publication year 1995 Abstract The balance of tissue-type plasminogen activator (t-PA) production and degradation determines its concentration in blood and tissues. Disturbance of this balance may result in either increased or decreased proteolysis. In the present study, we identified the receptor systems involved in the degradation of t-PA by human monocytes/macrophages in culture. Monocytes were cultured and became macrophages within 2 days. At 4°C, 125I-t-PA bound to macrophages with high (apparent dissociation constant [kd], 1 to 5 nmol/L) and low affinity (kd > 350 nmol/L). At 37°C, the cells internalized and degraded t-PA via the high affinity binding sites, which were partially inhibited by mannan. The low affinity binding sites were 6-aminohexanoic acid-inhibitable and not involved in t-PA degradation. Degradation of t-PA was upregulated during differentiation of monocytes to macrophages. Dexamethasone further upregulated the mannan-inhibitable t-PA degradation. Lipopolysaccharide downregulated both mannan-inhibitable and non-mannan- inhibitable t-PA degradation. Non-mannan-inhibitable degradation was completely blocked by recombinant 39-kD receptor-associated protein (RAP, inhibitor of lipoprotein receptor-related protein [LRP]), whereas mannan- inhibitable degradation was blocked by the addition of a monoclonal antibody against the mannose receptor. No differences between the degradation of t-PA and functionally inactivated t-PA were observed. We conclude that human monocyte-derived macrophages are able to bind, internalize, and degrade t- PA. Degradation of t-PA does not require complex formation with plasminogen activator inhibitors. The macrophages use two independently regulated receptors, namely, the mannose receptor and LRP, for the uptake and degradation of t-PA. Chemicals/CAS: aminocaproic acid, 1319-82-0, 60-32-2; tissue plasminogen activator, 105913-11-9; Dexamethasone, 50-02-2; LDL-Receptor Related Protein 1; Lipopolysaccharides; mannose receptor; Receptors, Cell Surface; Receptors, Immunologic; Tissue Plasminogen Activator, EC 126.96.36.199 Subject Biologyaminocaproic acidlipopolysaccharidelow density lipoprotein receptormannose receptorreceptor proteintissue plasminogen activatorarticlecontrolled studyhemostasishumanhuman cellmacrophagemolecular interactionnormal humanpriority journalprotein degradationreceptor affinityCell DifferentiationCells, CulturedDexamethasoneHumanLDL-Receptor Related Protein 1LipopolysaccharidesMacrophagesMonocytesReceptors, Cell SurfaceReceptors, ImmunologicSupport, Non-U.S. Gov'tTissue Plasminogen Activator To reference this document use: http://resolver.tudelft.nl/uuid:b311f6fe-bdc1-45bf-9615-03666a388552 TNO identifier 232914 ISSN 0006-4971 Source Blood, 86 (9), 3421-3427 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.