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*
Department of Molecular and Cellular Biology, Max Planck Institute for Physiological and Clinical Research, Bad Nauheim, Germany;
Institute of Pharmacology and Toxicology, University of Erlangen, Erlangen, Germany; and
Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
Endothelial activation is an important feature of many inflammatory
diseases and has been implicated as the cause of vascular complications
in disorders such as diabetes, atherosclerosis, and transplant
rejection. One of the most potent activators of the endothelium is TNF,
which can also be expressed by endothelial cells, causing a permanent,
autocrine stimulatory signal. To establish a model of continuous
endothelial activation and to elucidate the role of endothelial derived
TNF in vivo, we generated transgenic mice expressing a noncleavable
transmembrane form of TNF under the control of the endothelial-specific
tie2 promoter. Adult tie2-transmembrane TNF-transgenic mice developed
chronic inflammatory pathology in kidney and liver, characterized by
perivascular infiltration of mononuclear cells into these organs. Along
with the infiltrate, an up-regulation of the adhesion molecules ICAM-1
and VCAM-1, but not E-selectin, in the endothelium was observed.
Despite predisposition to chronic inflammation these mice were
protected from immune-mediated liver injury in a model of Con A-induced
acute hepatitis. Although the blood levels of soluble TNF and IFN-
were increased in transgenic animals after challenge with Con A, no
damage of hepatocytes could be detected, as assessed by the lack of
increase in plasma transaminase activities and the absence of TUNEL
staining in the liver. We conclude that expression of transmembrane TNF
in the endothelium causes continuous endothelial activation, leading to
both proinflammatory and protective events.
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