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Tumor necrosis factor alpha induces endothelial galactosyl transferase
activity and verocytotoxin receptors. Role of specific tumor necrosis
factor receptors and protein kinase C
NC van de Kar, T Kooistra, M Vermeer, W Lesslauer, LA Monnens and VW van Hinsbergh
Gaubius Laboratorium TNO-PG, Leiden, The Netherlands.
Infections with verocytotoxin (VT) producing Escherichia coli have been
strongly implicated in the epidemic form of hemolytic uremic syndrome
(HUS). Endothelial damage plays a central role in the pathogenesis of HUS.
In vitro studies have shown that VT can damage endothelial cells after
interaction with its cellular receptor globotriaosylceramide (GbOse3cer).
Cytokines, such as tumor necrosis factor alpha (TNF alpha) and
interleukin-1 (IL-1) can potentiate the toxic effect of VT by inducing a
protein-synthesis dependent increase in VT receptors on endothelial cells.
In this study, the mechanisms underlying the increase in endothelial VT
receptors induced by TNF alpha were studied in more detail. To investigate
which proteins were involved in this induction, endothelial cells were
incubated with and without TNF alpha in the presence of 14C-galactose or
14C-glucose. Thin-layer chromatography (TLC) analysis of the glycolipid
extracts of these cells demonstrated a markedly enhanced incorporation of
14C-galactose in GbOse3cer and other galactose-containing glycolipids,
suggesting that TNF alpha enhanced galactosyl-transferase activity. To
examine the role of the two recently cloned TNF-receptors (TNFR-p75 and
TNFR-p55) in the TNF alpha-induced increase in GbOse3cer in human
endothelial cells, cells were incubated with TNF alpha, the TNFR-p55
selective R32W-S86T- TNF alpha-mutant, or the TNFR-p75 selective
D143N-A145R-TNF alpha- mutant. The effect of TNF alpha activation,
determined by binding- experiments with 125I-VT-1, could be largely, but
not completely mimicked by R32W-S86T-TNF alpha. Although incubation of
cells with D143N-A145R-TNF alpha did not show an increase in VT-1 binding,
the monoclonal antibody utr-1, which prevents binding to TNFR-p75,
decreased the TNF alpha-induced VT-1 binding. Activation of protein kinase
C (PKC) by phorbol ester increases the expression of VT-1 receptors; this
effect was prevented by the PKC inhibitor Ro31-8220 and by homologous
desensitization by pretreatment with phorbol ester. In contrast, the
presence of the protein kinase inhibitor Ro31-8220 or desensitization of
PKC activity reduced the TNF alpha-induced increase in VT-1 receptors
maximally by 50% and 24%, respectively. Comparable reductions in overall
protein synthesis and the synthesis of E-selectin and plasminogen activator
inhibitor-1 (PAI-1) were observed. This suggests an effect on general
protein synthesis rather than a specific effect of PKC in the signal
transduction pathway, by which TNF alpha induces VT-1 receptors. Our
results indicate that TNF alpha can increase the VT-1 receptors on
endothelial cells by inducing galactosyl- transferase activity, that this
action of TNF alpha mainly occurs via the TNFR-p55; and that PKC activation
increases expression of VT-1 receptors by a separate mechanism that acts
additively to the TNF alpha- induced increase in VT-1 receptors.
Volume 85,
Issue 3,
pp. 734-743,
02/01/1995
Copyright © 1995 by The American Society of Hematology
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