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Monocyte tissue factor induction by lipopolysaccharide (LPS): dependence on
LPS-binding protein and CD14, and inhibition by a recombinant fragment of
bactericidal/permeability-increasing protein
K Meszaros, S Aberle, R Dedrick, R Machovich, A Horwitz, C Birr, G Theofan and JB Parent
XOMA Corp, Berkeley, CA 94710.
Mononuclear phagocytes, stimulated by bacterial lipopolysaccharide (LPS),
have been implicated in the activation of coagulation in sepsis and
endotoxemia. In monocytes LPS induces the synthesis of tissue factor (TF)
which, assembled with factor VII, initiates the blood coagulation cascades.
In this study we investigated the mechanism of LPS recognition by
monocytes, and the consequent expression of TF mRNA and TF activity. We
also studied the inhibition of these effects of LPS by rBPI23, a 23-kD
recombinant fragment of bactericidal/permeability increasing protein, which
has been shown to antagonize LPS in vitro and in vivo. Human peripheral
blood mononuclear cells, or monocytes isolated by adherence, were
stimulated with Escherichia coli O113 LPS at physiologically relevant
concentrations (> or = 10 pg/mL). The effect of LPS was dependent on the
presence of the serum protein LBP (lipopolysaccharide-binding protein), as
shown by the potentiating effect of human recombinant LBP or serum.
Furthermore, recognition of low amounts of LPS by monocytes was also
dependent on CD14 receptors, because monoclonal antibodies against CD14
greatly reduced the LPS sensitivity of monocytes in the presence of serum
or rLBP. Induction of TF activity and mRNA expression by LPS were inhibited
by rBPI23. The expression of tumor necrosis factor showed qualitatively
similar changes. Considering the involvement of LPS-induced TF in the
potentially lethal intravascular coagulation in sepsis, inhibition of TF
induction by rBPI23 may be of therapeutic benefit.
Volume 83,
Issue 9,
pp. 2516-2525,
05/01/1994
Copyright © 1994 by The American Society of Hematology

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