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Contact activation triggers stimulation of the monocyte 5-lipoxygenase
pathway via plasmin
I Weide, J Romisch and T Simmet
Department of Pharmacology and Toxicology, Ruhr University, Bochum,
Germany.
The purpose of this study was to characterize the stimulus that activates
the 5-lipoxygenase pathway in human peripheral monocytes (PM) during the
process of contact activation. Incubation of PM, but not of
polymorphonuclear leukocytes (PMN), in contact-activated, recalcified
plasma induced a time-dependent release of leukotrienes (LT). The presence
of platelets was required for the generation of cysteinyl-LT, but LTB4
formation also proceeded in their absence, although to a lesser extent.
Plasmin, presumably generated via the intrinsic fibrinolytic pathway, was
liable for the 5-lipoxygenase stimulation during contact activation
inasmuch as (1) the 5-lipoxygenase pathway in PM was stimulated by
contact-activated, recalcified, autologous or homologous plasma, but not by
factor XII-deficient or prekallikrein- deficient plasma; (2) lysine analogs
such as N alpha-acetyl-L-lysine, 6- aminohexanoic acid (6-AHA), or trans-4-
(aminomethyl)cyclohexane-1- carboxylic acid (t-AMCA), which inhibit
plasmin(ogen) binding to PM plasmin(ogen) binding sites,
concentration-dependently reduced the cysteinyl-LT release; (3) plasminogen
activators such as urokinase or streptokinase concentration-dependently
enhanced the cysteinyl-LT release up to 10 and 1,000 IU/mL, respectively,
while higher concentrations were less effective leading to bell-shaped
concentration- response curves; (4) plasmin inhibitors such as aprotinin or
alpha 2- antiplasmin concentration-dependently inhibited the cysteinyl-LT
release; and (5) preincubation of plasma with monoclonal antibodies
directed against plasminogen and capable of preventing plasminogen
activation blocked the contact-mediated 5-lipoxygenase stimulation.
Moreover, incubation of PM with plasmin, but not with plasma kallikrein, in
Hanks' balanced salt solution (HBSS)-bovine serum albumin (BSA) 0.4%
triggered a concentration-dependent release of LTB4 up to 0.1 caseinolytic
units (CU)/mL, with higher concentrations being less effective. By
contrast, release of cyclooxygenase metabolites such as thromboxane (TX) B2
and prostaglandin (PG) E2 was not stimulated by plasmin, indicating
specificity for the 5-lipoxygenase pathway. With plasmin as a hitherto
unknown stimulus of the 5-lipoxygenase pathway in PM, a novel link between
contact activation and inflammation has been established.
Volume 83,
Issue 7,
pp. 1941-1951,
04/01/1994
Copyright © 1994 by The American Society of Hematology
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