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Increase in cytosolic calcium upregulates the synthesis of type 1
plasminogen activator inhibitor in the human histiocytic cell line U937
F Peiretti, C Fossat, F Anfosso, MC Alessi, M Henry, I Juhan-Vague and G Nalbone
CJF INSERM 93-12, Laboratoire d'Hematologie, Faculte de Medecine,
Marseille, France.
In the U937 histiocytic cell line, we investigated the effect of
calcium-mobilizing agents with or without tumor necrosis factor-alpha (TNF)
on the regulation of the synthesis of plasminogen activator inhibitor-type
1 (PAI-1). Cultured U937 cells were stimulated with ionophore A23187 and
thapsigargin with or without TNF. The response was analyzed in terms of
cytosolic calcium mobilization, PAI-1 accumulation in the medium, and PAI-1
mRNA expression. The study was extended to urokinase (uPA) secretion and
surface expression of its receptor (uPAR). Using Fluo-3 as a
calcium-indicator dye to measure cytosolic calcium mobilization, we showed
by flow cytometry that both agents mobilized calcium in a dose-dependent
manner. TNF provoked a slight calcium mobilization that was also observed
by digital imaging microscopy. Association of TNF with the
calcium-mobilizing agents potentiated the calcium mobilization. Both
calcium-mobilizing agents induced at 18 hours a dose-dependent accumulation
of PAI-1 in culture medium, whereas uPA was not affected. TNF alone induced
a more marked accumulation of PAI-1 than of uPA. Association of TNF with
the agents induced a PAI-1 response that was more than additive of the two,
whereas the secretion of uPA was not enhanced. Membrane expression of uPAR,
measured by flow cytometry, tended to be slightly augmented by the
calcium-mobilizing agents only. All the treatments resulted in a
significant increase in PAI-1 mRNA level at 3 hours after the stimulation,
which was very marked when calcium-mobilizing agents were present.
Incubation of U937 cells in a calcium-free medium totally prevented both
the mRNA expression and accumulation of PAI-1 induced by calcium-mobilizing
agents and, to lesser extent, that induced by TNF. The increase in PAI-1
mRNA expression did not require de novo protein synthesis, as cycloheximide
did not suppress the increase in PAI-1 mRNA induced by calcium-mobilizing
agents. It is concluded that, in U937 cells, calcium triggers a pathway
that upregulates PAI-1 synthesis and positively interacts with the
TNF-induced pathway that stimulates PAI-1 synthesis. As uPA and uPAR were
differently affected, it is suggested that an increase in cytosolic calcium
leads to a reduced pericellular proteolysis.
Volume 87,
Issue 1,
pp. 162-173,
01/01/1996
Copyright © 1996 by The American Society of Hematology
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