Opposing effects of oestradiol and progesterone on intracellular pathways and activation processes in the oxidative stress induced activation of cultured rat hepatic stellate cells

Abstract

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 b and are also activated by ROS. Aims: 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-b1 (TGFb1) 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-b1 expression and HSC activation, and fibrogenic effects were inhibited by oestradiol. Conclusion: 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-b1 expression and HSC activation, whereas progesterone acts in opposition to the favourable effects of oestradiol and its effects are blocked by oestradiol.

Multimodal Regulation of NET Formation in Pregnancy: Progesterone Antagonizes the Pro-NETotic Effect of Estrogen and G-CSF

“…Additionally, phagocytosis seems to negatively regulate NETosis (23). Our data indicate that progesterone downregulates ROS production in neutrophils, which is in concordance to previous studies showing that progesterone is effective in reducing ROS and NO generation driven by estradiol (47, 48). The observed inhibition of ROS production occurs most probably in favor of a significant shift towards the involvement of calcium signaling and PAD4 mobilization, which most probably promotes phagocytosis rather than degranulation or formation of NETs (20).…”

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

“…Similar doses of 17-estradiol have also been previously used in both hepatic stellate cells [18] and hepatocytes [20] in studies about protection against oxidative stress.…”

“…In our study, 17 β estradiol, was used at a concentration range, amounting to 10 −9 –10 −7 M, which can commonly be found in menstrual/menopausal women [18, 19]. Similar doses of 17-estradiol have also been previously used in both hepatic stellate cells [18] and hepatocytes [20] in studies about protection against oxidative stress.…”

“…Although mild liver injury usually results in an almost complete resolution, persistence of the original insult causes prolonged activation of tissue repair mechanisms, leading to hepatic fibrosis. Collagen is mainly produced by HSCs, which are regarded as the primary target for inflammatory and peroxidative stimuli and are transformed into myofibroblastic-like cells, which are able to synthesize α-SMA [18]. …”

Examining Potential Therapies Targeting Myocardial Fibrosis through the Inhibition of Transforming Growth Factor-Beta 1

“…1). Previous studies have similarly shown NO may suppress NADPH oxidase thereby providing a link between NO and TGF-β 1 inhibition [15,94,95,96,97,98]. …”