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Role of protein kinase C in tumor necrosis factor induction of endothelial
cell urokinase-type plasminogen activator
MJ Niedbala and M Stein-Picarella
Institute of Inflammation and Autoimmunity, Miles Research Center, Miles
Inc, West Haven, CT 06516.
Tumor necrosis factor (TNF) can promote endothelial cell transcription,
synthesis, and secretion of urokinase plasminogen activator (uPA)
augmenting extracellular matrix remodeling and influencing cellular
differentiation. In this report, the role of the protein kinase C (PKC)
pathway in mediating TNF induction of uPA in human umbilical vein
endothelial cells is described. The PKC inhibitors (H-7, staurosporine, and
calphostin C), but not HA-1004, inhibited TNF-induced uPA expression,
synthesis, and secretion in a dose-dependent manner. Analysis of cell-free
conditioned medium obtained from PKC inhibitor- treated cultures by
micro-enzyme-linked immunosorbent assay methodologies using uPA- and
plasminogen activator inhibitor type 1 (PAI-1)-specific monoclonal
antibodies indicate that the decrease in uPA activity observed by sodium
dodecyl sulfate-polyacrylamide gel electrophoresis zymography was a direct
result of decreased extracellular uPA antigen and not a consequence of
increased PAI-1 antigen. The effect of PKC inhibitors was specific for
TNF-mediated increased uPA expression because cytokine induction of PAI-1
was not influenced by these agents. Northern blot analyses also showed that
PKC inhibitor treatment of endothelial cells resulted in a decreased
steady- state level of uPA mRNA with no measurable change in PAI-1 mRNA in
cultures incubated with TNF. Downregulation of cellular PKC by 18 hours of
phorbol myristate acetate (PMA) pretreatment of endothelial cell cultures
abolished TNF-mediated extracellular uPA induction. This effect was
specific for PMA because 4-alpha PMA pretreatment of cells, which does not
stimulate PKC, was ineffective in altering TNF induction of endothelial
cell uPA. Induction of PKC directly with PMA, mezerein, and
(-)-octylindolactam V increased endothelial cell levels of extracellular
uPA in a time- and dose-dependent manner. In addition, this increase in
endothelial cell extracellular uPA activity mediated by PKC agonists could
be inhibited with PKC inhibitors. Endothelial cells treated with TNF
acquire the ability to invade extracellular matrix and reorganize into
tube-like structures when grown on Matrigel- coated culture dishes, a
behavior blocked by H-7, but not by HA 1004. In summary, these data
implicate a role for the PKC pathway in the TNF- mediated induction of uPA
expression, subsequent matrix remodeling, and the formation of tube-like
structures, a process important in neovascularization, wound healing, and
leukocyte extravasation.
Volume 81,
Issue 10,
pp. 2608-2617,
05/15/1993
Copyright © 1993 by The American Society of Hematology
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