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Refractory period phenomenon in the induction of tissue factor expression
on endothelial cells
N Busso, S Huet, E Nicodeme, J Hiernaux and F Hyafil
Laboratories GLAXO, Centre de Recherches, Les Ulis, France.
Tissue factor (TF) is the first factor of the extrinsic pathway of
coagulation. Normally, TF is not expressed on the surface of endothelial
cells. However, expression of TF can be induced in these cells in response
to stimulation by diverse inflammatory mediators such as interleukin-1 beta
(IL-1 beta), tumor necrosis factor-alpha (TNF- alpha), lipopolysaccharide
(LPS), and phorbol 12-myristate 13-acetate (PMA). We have studied the
effect of these mediators on the kinetics of the induction of TF-related
procoagulant activity (PCA) on human umbilical vein endothelial cells
(HUVECs). PCA is transiently induced on HUVECs, attaining a peak some 4 to
8 hours after addition of inflammatory agents, with maximal accumulation of
TF messenger RNA (mRNA) occurring 3 to 5 hours earlier. Because the
expression of PCA by treated HUVECs returns to basal levels by 20 to 30
hours, we examined the response of these cells to a second inflammatory
stimulus. Continuous incubation of cells with a single inflammatory agent
for 24 to 48 hours induces a hyporesponsive state with respect to the
reinduction of TF expression by the same agent (14% of the initial
stimulation for IL-1 beta, 39% for TNF-alpha 30% for LPS, and 7% for PMA).
Such a diminution in PCA was also observed in the levels of TF mRNA. By
contrast, pretreatment of HUVECs with one agent did not dramatically affect
the reinduction of TF by any of the three other factors. We subsequently
focused our attention on the induction of the autologous refractory period
by IL-1 beta. De novo protein synthesis was not required during the
preincubation of ECs for hyporesponsiveness to be observed. The
establishment of the refractory state did not depend on the downmodulation
of IL-1 beta receptor affinity or expression. Moreover, pretreatment of
HUVECs with IL-1 beta increased prostacyclin (PGI2) production in response
to a second stimulation by IL-1 beta, although such cells were unable to
reexpress TF under the same conditions. This result suggests that distinct
secondary messenger pathways are involved in TF induction and PGI2
synthesis by IL-1 beta in HUVECs.
Volume 78,
Issue 8,
pp. 2027-2035,
10/15/1991
Copyright © 1991 by The American Society of Hematology
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