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Tumor necrosis factor induction of endothelial cell urokinase-type
plasminogen activator mediated proteolysis of extracellular matrix and its
antagonism by gamma-interferon
MJ Niedbala and MS Picarella
Institute of Arthritis and Autoimmunity, Miles Research Center, Miles Inc,
West Haven, CT. 06516.
Tumor necrosis factor (TNF) has a profound capacity to alter the
endothelial cell phenotype that includes morphologic and functional changes
that may be central for proinflammatory processes. Recent observations have
indicated that TNF can promote the synthesis and secretion of urokinase
plasminogen activator (uPA) in low passage human endothelial cells that
normally release little uPA. In this report we have confirmed and expanded
upon these initial observations in human endothelial cells and describe the
ability of gamma-interferon (gamma- IFN) to inhibit TNF-induced uPA
synthesis and secretion in a dose- dependent manner (0.025 to 25 ng/mL).
Analysis of cell-free conditioned medium derived from gamma-IFN-treated
cultures by micro-enzyme-linked immunosorbent assay (ELISA) methodologies
using uPA- and plasminogen activator inhibitor type 1 (PAI-1)-specific
monoclonal antibodies (MoAbs) indicate that the decrease in uPA activity
observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS-PAGE) zymography is a direct result of a decrease in extracellular uPA
antigen and is not a consequence of increased PAI-1 antigen. These findings
are supported by Northern blot analyses that indicate that gamma-IFN
treatment of endothelial cells resulted in a decreased steady state level
of uPA messenger RNA (mRNA) with no measurable change in PAI-1 mRNA. This
inhibitory response is specific for gamma-IFN because alpha-IFN fails to
elicit a similar inhibitory response. In addition, TNF augmented
extracellular proteolysis of radiolabeled subendothelial extracellular
matrix (ECM) in a dose-dependent manner. The observed increase in ECM
degradation mediated by TNF treatment of endothelial cells was dependent on
the presence of plasminogen and could be inhibited by an anticatalytic uPA
MoAb implying the requirement of proteolytically active uPA in this
process. gamma-IFN (25 ng/mL) treatment of endothelial cells antagonized
TNF-promoted degradation of radiolabeled ECM at a concentration that
completely inhibited TNF- mediated uPA expression and activity. In
addition, endothelial cells treated with TNF (18 hours) displayed the
ability to invade ECM and reorganize individual cells into tube-like
structures that were not evident in untreated control cultures when grown
on Matrigel-coated culture dishes. gamma-IFN treatment of endothelial cells
propagated on Matrigel was observed to inhibit TNF-mediated ECM invasion
and tube formation at concentrations that were analogous to those required
for the inhibition of uPA expression and activity. In summary, these
observations suggest a novel homeostatic control mechanism for endothelial
cell regulation of subendothelial ECM degradation promoted by TNF and
inhibited by gamma-IFN.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 79,
Issue 3,
pp. 678-687,
02/01/1992
Copyright © 1992 by The American Society of Hematology
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