Inhibitory effect of a soluble transforming growth factor beta type II receptor on the activation of rat hepatic stellate cells in primary culture.
OBJECTIVE
Oxidative stress, including the generation of reactive oxygen species (ROS) that acts as a signaling mediator for transforming growth factor (TGF)-beta, plays a key role in hepatic fibrosis. Hepatic stellate cells (HSCs) produce and respond to TGF-beta in an autocrine manner with increased collagen expression. It has previously been reported that the adenovirus-mediated overexpression of a soluble receptor against the extracellular domain of the TGF-beta type II receptor prevents hepatofibrogenesis in vivo, although its inhibitory role and mechanism in HSC activation remains to be elucidated.


METHODS
In this study, we report on an examination of the actual role of TGF-beta inhibition on oxidative stress and the activation of cultured rat HSCs, using the adenovirus-mediated soluble TGF-beta type II receptor.


RESULTS
This soluble receptor secreted from the adenovirus-infected cells binds to TGF-beta. Infection of HSCs with this adenovirus attenuated intracellular levels of TGF-beta1 mRNA and protein, NADH oxidative activity, ROS generation and lipid peroxidation, and prevented HSC activation.


CONCLUSIONS
These findings suggest that this adenovirus-mediated soluble TGF-beta receptor may lead to an interruption of the TGF-beta autocrine loop in activated HSC, in part, by inhibiting oxidative stress.
Department of Digestive and Cardiovascular Medicine, Tokushima University School of Medicine, Kuramoto-cho, Tokushima 770-8503, Japan.
Xuezhi
X
Cui
Ichiro
I
Shimizu
Guangming
G
Lu
Mina
M
Itonaga
Hiroshi
H
Inoue
Masayuki
M
Shono
Katsuyoshi
K
Tamaki
Hiroshi
H
Fukuno
Hikaru
H
Ueno
Susumu
S
Ito
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D015227:Lipid Peroxidation / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics; D053773:Transforming Growth Factor beta1
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009243:NAD; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II