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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
F Noorman, EA Braat and DC Rijken
Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands.
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 degrees 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 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 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.
Volume 86,
Issue 9,
pp. 3421-3427,
11/01/1995
Copyright © 1995 by The American Society of Hematology
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