Estrogen protects against postpartum Concanavalin A-induced hepatitis by promoting intrahepatic CD4⁺CD25⁺ Treg expansion through activation of the PI3K/Akt signaling pathway in HBV-Tg mice

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.