Opposing effects of oestradiol and progesterone on intracellular pathways and activation processes in the oxidative stress induced activation of cultured rat hepatic stellate cells.
BACKGROUND
Oxidative stress, including the generation of reactive oxygen species (ROS), is involved in hepatofibrogenesis. The authors' previous studies have shown that oestradiol suppresses hepatic fibrosis in animal models and attenuates the activation of cultured rat hepatic stellate cells (HSCs), which possess oestrogen receptor subtype beta and are also activated by ROS.


OBJECTIVE
To define the mechanisms by which female sex hormones play an antifibrogenic role in activated HSCs, the effects of oestradiol and progesterone on ROS generation processes and intracellular pathways, leading to the activation of HSCs undergoing oxidative stress, was examined.


METHODS
HSCs, isolated from rats, were cultured for 7 days with oestradiol or progesterone for 24 hours as pretreatment, and oxidative stress was then induced by exposure to low doses of hydrogen peroxide for another 24 hours.


RESULTS
Oestradiol inhibited ROS generation and antioxidant enzyme loss via the suppression of NADH/NADPH oxidase activity, and attenuated hydrogen peroxide induced transforming growth factor-beta1 (TGF-beta1) expression, HSC proliferation and transformation, and the activation of mitogen activated protein kinase (MAPK) pathways and transcription factors. Progesterone exerted a stimulatory effect through the progesterone receptor on the induction of ROS generation processes and intracellular pathways, resulting in TGF-beta1 expression and HSC activation, and fibrogenic effects were inhibited by oestradiol.


CONCLUSIONS
These findings show for the first time that oestradiol inhibits the activation of transcription factors by suppressing ROS generation processes and the MAPK pathways, and inactivates the downstream transcription processes involved in TGF-beta1 expression and HSC activation, whereas progesterone acts in opposition to the favourable effects of oestradiol and its effects are blocked by oestradiol.
Itagaki
T
T
Department of Digestive and Cardiovascular Medicine, Tokushima University Graduate School, Kuramoto-cho, Tokushima 770-8503, Japan.
Shimizu
I
I
Cheng
X
X
Yuan
Y
Y
Oshio
A
A
Tamaki
K
K
Fukuno
H
H
Honda
H
H
Okamura
Y
Y
Ito
S
S
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011374:Progesterone / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D011980:Receptors, Progesterone; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009243:NAD; D011374:Progesterone; D004958:Estradiol; D006861:Hydrogen Peroxide; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D020928:Mitogen-Activated Protein Kinases