Production of plasminogen activator inhibitor type-2 in human peripheral blood monocytes upregulated in vitro by the quinoline-3-carboxamide, Linomide

SummaryRegulation of cellular plasminogen activation is necessary for maintenance of tissue homeostasis. Despite increasing evidence for co-expression of tissue type plasminogen activator (tPA) and plasminogen activator inhibitor type-2 (PAI-2;SERPINB2) under patho/physiological conditions, the inhibition of cell-bound tPAmediated plasminogen activation by PAI-2 has not been addressed. Here we show that PAI-2 can inhibit cell-bound tPA activity in vitro and thus prevent plasmin formation. We also examined the potential involvement in this inhibition of the annexin II heterotetramer (AIIt), one of the many well characterized cell-surface co/receptors for tPA and plasminogen that efficiently promotes plasminogen activation. This receptor was of interest because AIIt has also been shown to directly bind PAI-2. Characterization of these potential interactions using purified protein systems revealed that PAI-2 directly bound AIIt via the p11 (S100A10) subunit. However, PAI-2 prevented AIIt/tPA-mediated plasminogen activation by its classic serpin inhibitory activity rather than through competition with tPA/plasminogen for binding. Further analysis showed that PAI-2 inhibited cell bound tPA-induced plasmin activity in both an AIIt-dependent and -independent manner. These data open new possibilities for further investigations regarding the regulation of cellular plasmin generation in vivo, especially in tissues where PAI-2 and tPA may be co-expressed.

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109 Plasminogen activator inhibitor (PAI) in human peripheral blood monocytes (MC)

Fibrinolysis and Proteolysis ◽

10.1016/0268-9499(88)90456-0 ◽

1988 ◽

Vol 2 ◽

pp. 48

Author(s):

J.C. Castellote ◽

P. Fabregas ◽

E. Grau

Keyword(s):

Plasminogen Activator ◽

Peripheral Blood ◽

Human Peripheral Blood ◽

Plasminogen Activator Inhibitor ◽

Blood Monocytes ◽

Peripheral Blood Monocytes ◽

Activator Inhibitor

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The Distribution of the Secreted and Intracellular Forms of Plasminogen Activator Inhibitor 2 (PAI-2) in Human Peripheral Blood Monocytes Is Modulated by Serum

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615070 ◽

1998 ◽

Vol 79 (04) ◽

pp. 813-817 ◽

Cited By ~ 7

Author(s):

Helen Ritchie ◽

Nuala Booth

Keyword(s):

Plasminogen Activator ◽

Peripheral Blood ◽

Human Peripheral Blood ◽

Calf Serum ◽

Plasminogen Activator Inhibitor ◽

Blood Monocytes ◽

Peripheral Blood Monocytes ◽

Activated Monocytes ◽

Culture Supernatants ◽

Activator Inhibitor

SummaryPlasminogen activator inhibitor 2 (PAI-2) is produced by activated monocytes in two forms, intracellular and secreted. We have studied the distribution of these two forms in unstimulated human peripheral blood monocytes and after stimulation by thrombin. Fetal calf serum (FCS) in the culture medium was absolutely necessary for accumulation of intracellular PAI-2; but not for synthesis and secretion. Even at a concentration as low as 0.1%, FCS restored accumulation of intra-cellular PAI-2. Increasing concentrations of FCS resulted in an increase in the ratio of intracellular to secreted PAI-2. The factor that promoted accumulation of intracellular PAI-2 was not a platelet product. Failure of monocytes to accumulate PAI-2 did not reflect leakage due to cell death, as assessed by LDH in culture supernatants. We propose that accumulation of intracellular PAI-2 is not simply due to poor secretion, but is an active process that is modulated by factor(s) found in serum.

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