Chronic inflammation and protection from acute hepatitis in transgenic mice expressing TNF in endothelial cells.
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Chronic inflammation and protection from acute hepatitis in transgenic mice expressing TNF in endothelial cells. / Willuweit, A; Sass, G; Schöneberg, A; Eisel, U; Tiegs, Gisa; Clauss, M.
in: J IMMUNOL, Jahrgang 167, Nr. 7, 7, 2001, S. 3944-3952.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Chronic inflammation and protection from acute hepatitis in transgenic mice expressing TNF in endothelial cells.
AU - Willuweit, A
AU - Sass, G
AU - Schöneberg, A
AU - Eisel, U
AU - Tiegs, Gisa
AU - Clauss, M
PY - 2001
Y1 - 2001
N2 - 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-gamma 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.
AB - 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-gamma 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.
KW - Animals
KW - Mice
KW - Chronic Disease
KW - Up-Regulation
KW - Mice, Transgenic
KW - Acute Disease
KW - Liver/metabolism/pathology
KW - Concanavalin A
KW - RNA, Messenger/biosynthesis
KW - Cell Adhesion Molecules/biosynthesis
KW - Drug-Induced Liver Injury/metabolism/pathology/therapy
KW - Endothelium, Vascular/metabolism
KW - Inflammation/chemically induced/metabolism/pathology
KW - Kidney/metabolism/pathology
KW - Membrane Proteins/genetics/metabolism/physiology
KW - Receptor Protein-Tyrosine Kinases/genetics
KW - Receptor, TIE-2
KW - Tumor Necrosis Factor-alpha/genetics/metabolism/physiology
KW - Animals
KW - Mice
KW - Chronic Disease
KW - Up-Regulation
KW - Mice, Transgenic
KW - Acute Disease
KW - Liver/metabolism/pathology
KW - Concanavalin A
KW - RNA, Messenger/biosynthesis
KW - Cell Adhesion Molecules/biosynthesis
KW - Drug-Induced Liver Injury/metabolism/pathology/therapy
KW - Endothelium, Vascular/metabolism
KW - Inflammation/chemically induced/metabolism/pathology
KW - Kidney/metabolism/pathology
KW - Membrane Proteins/genetics/metabolism/physiology
KW - Receptor Protein-Tyrosine Kinases/genetics
KW - Receptor, TIE-2
KW - Tumor Necrosis Factor-alpha/genetics/metabolism/physiology
M3 - SCORING: Journal article
VL - 167
SP - 3944
EP - 3952
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 7
M1 - 7
ER -
