Involvement of Protein Kinase C in Cytokine-Induced Tissue Factor Production in Human Vascular Endothelial Cells
作者:
PoCheng,
ArlethAnthony J.,
OhlsteinEliot H.,
期刊:
Endothelium
(Taylor Available online 1994)
卷期:
Volume 2,
issue 3
页码: 209-216
ISSN:1062-3329
年代: 1994
DOI:10.3109/10623329409053377
出版商: Taylor&Francis
关键词: PKC;Procoagulant;activities in;tissue injury;Protein kinase inhibitors;Tissue factor;Vascular endothelial cells
数据来源: Taylor
摘要:
Cultured vascular endothelial cells demonstrate procoagulant activity following stimulation by cytokines and other inflammatory agents. Tissue factor is a cell surface membrane protein, which functions as a receptor and essential cofactor for Factor VII triggering the blood coagulation process. The mechanism(s) by which cytokine/inflammatory agents stimulate the production of tissue factor is still unclear. We hypothesized that protein kinase C (PKC) may be involved in cytokine/inflammatory agent-induced up-regulation of tissue factor in human vascular endothelial cells. The production of tissue factor by human umbilical endothelial cells (HUVEC) was enhanced markedly (5-10 fold) by TNFα(100 U/ml), IL-1 (10 U/ml) or LPS (100 ng/ml). Phorbol esters (PMA or PDBu) stimulated the production of tissue factor by HUVEC in a concentration-dependent manner, while the biologically inactive analog of PDBu, 4α-PDBu was inactive. Maximal stimulation by PMA (10-12 fold) was obtained at 200 nM and the ED50was 50 nM. PDBu was 10 times less active than PMA with an ED50of 500 nM. The non-phorbol activator of PKC, octylinolactam V also stimulated the production of tissue factor in a concentration-dependent manner and maximal stimulation (15 fold) was obtained at 3μM. Octylindolactam V-, cytokine-, or LPS-stimulated tissue factor production was blocked (50-100%) by the relatively selective PKC inhibitor H-7 (10-30μM). The rank order potencies of various kinase inhibitors tested on TNFα-induced tissue factor production was staurosporine>calphostin C>H-7>HA 1004 = H-8. The present study provides evidence for the involvement of endothelial PKC in cytokine-induced up-regulation of tissue factor production.
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