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

The balance of tissue-type plasminogen activator (t-PA) production and degradation determines its concentration in blood and tissues, Distur bance of this balance may result in either increased or decreased prot eolysis. In the present study, we identified the receptor systems invo lved in the degradation of t-PA by human monocytes/macrophages in cult ure. Monocytes were cultured and became macrophages within 2 days. At 4 degrees C, I-125-t-pA bound to macrophages with high (apparent disso ciation constant [kd], 1 to 5 nmol/L) and low affinity (kd > 350 nmol/ L). At 37 degrees 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 upregula ted during differentiation of monocytes to macrophages. Dexamethasone further upregulated the mannan-inhibitable t-PA degradation. Lipopolys accharide downregulated both mannan-inhibitable and non-mannan-inhibit able t-PA degradation. Non-mannan-inhibitable degradation was complete ly blocked by recombinant 39-kD receptor-associated protein (RAP, inhi bitor of lipoprotein receptor-related protein [LRP]), whereas mannan-i nhibitable degradation was blocked by the addition of a monoclonal ant ibody against the mannose receptor. No differences between the degrada tion of t-PA and functionally inactivated t-PA were observed. We concl ude that human monocyte-derived macrophages are able to bind, internal ize, and degrade t-PA. Degradation of t-PA does not require complex fo rmation with plasminogen activator inhibitors. The macrophages use two independently regulated receptors, namely, the mannose receptor and L RP, for the uptake and degradation of t-PA. (C) 1995 by The American S ociety of Hematology.