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 CD4CD25Foxp3 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 CD4CD25Foxp3Tregs 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 CD4CD25Foxp3Tregs in vivo.

RESULTS

A higher percentage of CD4CD25Foxp3Tregs 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 CD4CD25Foxp3 Tregs via the PI3K/Akt signaling cascade and participates in hepatitis immune regulation. Furthermore, E2 administration postpartum increased intrahepatic CD4CD25Foxp3Tregs 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.