Chronic inflammation and protection from acute hepatitis in transgenic mice expressing TNF in endothelial cells

Endothelial activation is an important feature of many inflammatory disease s and has been implicated as the cause of vascular complications in disorde rs such as diabetes, atherosclerosis, and transplant rejection. One of the most potent activators of the endothelium is TNF, which can also be express ed 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 th e endothelial-specific tie2 promoter. Adult tie2-transmembrane TNF-transgen ic mice developed chronic inflammatory pathology in kidney and liver, chara cterized by perivascular infiltration of mononuclear cells into these organ s. Along with the infiltrate, an up-regulation of the adhesion molecules IC AM-1 and VCAM-1, but not E-selectin, in the endothelium was observed. Despi te predisposition to chronic inflammation these mice were protected from im mune-mediated liver injury in a model of Con A-induced acute hepatitis. Alt hough the blood levels of soluble TNF and IFN-gamma were increased in trans genic animals after challenge with Con A, no damage of hepatocytes could be detected, as assessed by the lack of increase in plasma transaminase activ ities and the absence of TUNEL staining in the liver. We conclude that expr ession of transmembrane TNF in the endothelium causes continuous endothelia l activation, leading to both proinflammatory and protective events.