Abstract
Introduction:
Postpartum hepatitis flares have been commonly described, but the specific mechanism is unclear.
Objectives:
Our objective was to explore estrogen's role in postpartum hepatitis flares in HBV transgenic mice.
Methods:
The numbers of intrahepatic CD4+CD25+Foxp3+ regulatory T cells (Tregs) and the levels of the inhibitory cytokine IL-10 were determined in concanavalin A (Con A)-injected mice with and without estrogen injection postpartum. The role of intrahepatic CD4+CD25+Foxp3+Tregs in suppressing immune responses was investigated by systemically depleting intrahepatic CD25+ cells in mice treated with an anti-CD25 mAb. We employed the PI3K inhibitor LY294002 to investigate the function of the PI3K/Akt pathway in regulating the suppressive activity of intrahepatic CD4+CD25+Foxp3+Tregs in vivo.
Results:
A higher percentage of CD4+CD25+Foxp3+Tregs accumulated in the liver with increasing physiological E2 levels during pregnancy, declined sharply by day 7 postpartum. We discovered that estrogen regulates the proliferation and activation of intrahepatic CD4+CD25+Foxp3+ Tregs via the PI3K/Akt signaling cascade and participates in hepatitis immune regulation. Furthermore, E2 administration postpartum increased intrahepatic CD4+CD25+Foxp3+Tregs and inhibitory cytokine IL-10, which inhibit the immune clearance of CD8+ T cells and NK cells along with decreased cytotoxic cytokine IFN-γ and TNF-α levels.
Conclusion:
Estrogen protects against postpartum Con A-induced hepatitis by promoting intrahepatic CD4⁺CD25⁺ Treg expansion through activation of the PI3K/Akt signaling pathway in HBV-Tg mice.